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132 less dynamic


control of phase transitions

Cell Membranes cholesterol } glycolipids inhibittransitions


Compartments : allow for different environments diff . Cellfunction

less dynamic
,

plasma membrane ,ER . Golgi Apparatus . Nuclear Envelope constant body temp negates most thermal effect

compartmentalization Mosaic -

organization
basic structure } components domains officers .
unlike lipids } associated

bilayer of phospholipids NISA thick transmembrane


proteins
heads
hydrophilic Integrity
" "

Water loving phosphate Membrane


facetowards aqueous cytosol 's environment the cell is full t Charges } molecules that drives intro

lipid
"

Water bilayer little


hydrophobic fearingtails bilayer has structural Strength
"

]
proteins sugar
- -

Salts Etc
embedded
, ,

proteins
-

adherentlpartially Waterford mustbebalancedorcell bursts .

int .ORG/ternalsurfaceC glycoproteins carbohydrates) -

exchange of ions preferred -5


depolarizations repolarization

selectivity ) specificity of the interactions btwn proto

transmembrane :

partiallytotally across them embrace .


to fix this :
Deregulate intracellular ions

linked to ECM or int .

cytoskeleton prevents changes in osmotic


pressure
connection
physical across membrane preserve optimal biochemical environment

Lipids ionconc .

affects protein structure } function .

biochemical properties influence recover from ion


changes associated w/ nerve 's muse .

Which proteins can be inserted ,


Which drags function .

candiffuseacross Membrane Transport

protein mvtwlin Diane of the membrane .

Ion Channels :
properties
Viscosity Dater for Nat channel
ofbilayernloot highly selective particular ions ex insane
-

, .
,

Proteins
hydrated
?
hydrophobic 3 hydrophilic regions -

how is selectivity generated


functions : .

ionsizemattersizthesizefsecectivityotthechannd
transport C Nat ) ?
Selective etc ?
Why is the a
chanhelsobadfortvatfktions
-

ion channels 3 drug transporters the -0


Chargemakesitdtfficuttfortoionstogetacross
-

receptors 'Lsnsuxn,hGH ,
etc .
) -

Diffusion :
passive transport

peptide hormone growth random molecular mvtingaslliguicl


-

, hormones

( lung cancer ) ,
cell-cell tissue attach -
-

diffusion across amembrane

ment ,
platelet clotting ;
transmitting
.

simple :
through aonembrane protein channel or

signals across membrane . lipid bilayer


Cellfluid Mosaic Model facilitated intotsohetewlporter
-

requires protein that


.

?
Whats the fluid What's the mosaic
, aiasthepassagethroughamemrrane

fluid motion transitions in time 's


's phase organization uniportergsymport antipater
- '

lipids inbilayercanisyovewlintheplaneofthememb Simple Diffusion


'

.
:

lipids vary in biochemical characteristics and rates determined by conc ,


kinetic motion ; # of pores
"

phage
"

effect compound's lipid solubility

some are More mobile -

membrahephase hi -

lipid solubility C Nonpolar ) Ozcrosses readily

fluid like →
dynamic to -

not lipid soluble →


butwlhelpof protein channel

Some less mobile -

membrane phase gellike


,
thekineticmotionisleastlikeytovary
cont
Lecture 132 .
. .

Facilitated Diffusion

requires interaction w/ carrier protein →


change shape DIGITALIS :
Treats congestive heart failure

differs from simple diffusion inhibits Kt from binding in the NAY Kt ATPase
pump

leading

facilitated diffusion plateaus to a high intra -


Nat conc .

limiting # of
transport proteins 3 Nat exchanges w/ Cat in any direction using bi-directional

Active Transport anti porter

causing
"
intra cell increase activating actin T
against a
gradient } using energy .ca to , , contract .

°
7- ATP as of the heart
energy
-

20 ion gradient
-

Natl Kt ( Natha ATPase )


pump

EX .
Of 10 Active Transport

.
sites for binding 3N at

↳ domain ATPase fund


w/
.

Outer surface

2kt

Abundance correlates w/ cell function

Heart Cell 3 Neuron s look pumps

Energy use zion consequence

consumes 30% of while


Energy at rest
-

E released 310034 from ATP ADP conf


"

pump
change
→ →
. →

3 Nat out 32kt in


① ③


⑥ ⑤

1.

the
3 Nat can bind from the inside

2 ATP is
phosphorylated
.

3 .
Nat is released OUT of cell

4 When Nat is released protein reconfigures


, ,

the cell
allowing Kt to enter

5 .
Dephosphorylation
6 .
kit is released into the cell

A .

Natl Kt pump

EAT

B. Natfclucosesymport -520 AT
hi
Nat conc drives the of
uptake tTf
.

glucose
hi Glucose

C . Glucose Uni port → FD


5- 6611MHz

A-
Microfilaments -

Caltrans port
;
Stability easily assembled disassembled dynamic
.

-
-

cytomotilitytriggers Diameter -8hm smallest


OCCUrencl-foundinallcells.io?oO9oottotalproteinin -
he -

signalstromthe environment initiate mvt .

muscle
Chemical intoisreceivedbycellsurtace receptors

Lipid bilayer .

transmembrane protein hasanettracdl . MONOMER


protein
Globular - .

battin
domain Signals -

can Dass though the bilayer POLYMER f-actin # filamentous actin .

receptors actin
receive signals from hormones, growth factors 's bacterial peptides
join
monomers head head resulting in
-

polar
-
.

emir signals form chemical gradients I accessory .to


rminproteinsthat.me/pdriremonomer
.

activation off protein coupling Receptors


.

signal targeting Receptors polymer formation


-

.

Cause lcoittlocomeoutotthecellrscausing Actin Imicrofilaments


to DigitalisFROM Lett
.

polymerize
-

Actin Polymerization has Polarity itoendaddsl polymerizes motility) -


- MICRO filament Organization
Structuralsupport's
Variation
-0 end subtracts Idepolymerize)
.

actin based motion


ameboid bundles individual zparalklarrays
.

.
-

cell movement in response to chemotactic or tight 't dense protrusions of cell


haptotactil Stimulus Membrane called filopodia lnarrowlsilamellipo

Cellsmoveupagradienttowardshigherconc
resselwalkthrafonnectivetissuemovementriaml.RO
proteins
accessory
-

Chemotaxis -

.
Hlattrolefor

attractive factor insolation

filopodia
-

Wound fluid

branched
bbundkpolyfmers
macrophages migrating towards bacterial Proteins
.

WKROsslinking-haptotaxis.cm
lamellipodia
-
moveupagradienttowardattractirefaltortooundtoasurface
proteins onsurtaceot connectivetissue
polymers
-

networks -

crisscrossing microfilaments and


epithelial Cell
migrating inwoundbed
.

viscosity
otcytoplasm - cell
cell migration wound healing 's metastasis
.
.

Organized byassemblyldisassembly involved


.
.

tread milling
wlcytmotility -

movement microfilaments
.ee/lsmigratifgbeyondtumop
Polymerizing addingactinmonomersattopiusends
i
-

malignant
Metastasis -

depolymerizationremoving actin monomers @ -0 ends


-

thru connective tissue


cyclization of actin , gaining actinon cell edge , pushing
.

thruresselwalltocl.RU/ation
membrane forward -
extending stress fibers
-

filaments microtilamenttuessory Proteins

polymerization otactin treadmill ing Controlling microfilamentsfracture 's function


.
-

depolymerization removing actinmonomersatimnusenas


-

Polymerization

result netgainofactin
-

accessory proteins
-

@ cell edge
-

kinases diffkindswldiftsubstratesinditfceks
.

ettendsthetibersimoresthememb forward
Structural vinallinpgenesfortalinhge.es
.
-
-

Microfilaments 3 stepstomitigatioh -

toraactinin
Protrusion Attachment Retraction NOdesinanetwork-2waycommunicationinandoutoi.ae "
-

, ,
ractinfiberstsauessoryproteinstsintegrinssxcprotei

?
Whatlonsequencesoclurfromremovingnodes
nostructurd support
Cy to motility Triggers

signals from the environment initiate mvt .

Chemical into is received by cell surface receptors

Lipid bilayer -

transmembrane protein has an extra all .

domain Signals -

can pass though the


bilayer
receptors -

receive signals from hormones, growth factors 's bacterial peptides

emir signals form chemical gradients


.

activation of G protein coupling Receptors


.
.

signal targeting Receptors


CAUSE l Ca'T to come out of cell
is
the causing Act in (microfilaments
to polymerize
-

Act in Polymerization has Polarity → to end adds Ipolymerizes →


motility)
-0 end subtracts Ide polymerizes)

Actin based motion


ameboid
.

Cell movement in response to chemotactic OR


hate to tactic Stimulus

Chemotaxis
Cells -

move up a gradient towards higher .

of
attractive factor in solution
fluid

conc
filopodia
-

Wound

branched
b bundlepainters
macrophages migrating towards bacterial Proteins
.

W/ CROSS linking
naptotaxis cells move up a gradienttoward attractive factor bound to a surface
-

1am ell ipod la


Proteins on surface of
-

Connectivetissue
Polymers
epithelial
migrating in wound bed cell
.

microfilaments
Cell Migration wound healing y metastasis
.

migrating
.

malignant
metastasis -

cells beyond tumor


-

thru connective tissue


-

thru vessel wall to circulation


vessel walk thru connective tissue
-

Movement via
polymerization of actin -
treadmill ing
depolymerization I act in monomers at minus ends
removing
result net gin of actin
-

@ cell edge

extends the fibers y moves the men b.forward

Microfilaments -3 steps to mitigation


Protrusion Attachment Retraction
, ,
forward

ecellsinthemiddleotthecellbbundkpolyfm.rs
.

cytomotility Triggers .

signalstromthe environment initiate mrt .


lttendsthetibersimoresthememb
Microfilaments -3 Stepstomitigatioh

Chemical intoisreceivedbycellsurtace receptors Protrusion Attachment Retraction


, ,

Lipid bilayer transmembrane protein hasanettracdl ONPARWKLH


migration
.

Protrusion extension
domain signals
.

can Dass though the bilayer


-

receptors -

receive signals from hormones, growth factor bacterial peptides


i

actin polymerization atleadingedgeotmembrane-tamellipod.la 's filopodia


Attachment adhesion Plagues focal
emir signals form chemical gradients contact directcontwlenvironment
.
-
.
-

Stressfibersmadeupof microfilaments filamentous actin


-

ACTIVATION Off protein coupling Receptors Receptors


-

Signal targeting
'
.

CAUSE Cca'T
-

interaction sitewltransmemb integrin protein dimers


outofthecell.scausingactinlmicrofilamentt.to polymerize
.

come
-

Actin Polymerization has Polarity * vinculinttalin connect the connection wladhesionplaaues


-

to end adds Ipolymerizes


-

motility)
.
-
i -

release
-0 end subtracts Idepolymerize) environment
bhelpmakedirectcontactwtthe
Retraction adhesion plague disassembly
Altinbasedameboidmotion
-
:

cell movement in response to chemotactic or lntacellremoralottheadhesionplaguetromitstrailingends


Microfilaments -

Mvt
haptotactil Stimulus
Transientstructure contractile Rings .

chemotaxis -

.
.

incytokinesislateincelldivisionllytokinesis)

of
attractive factor insolation -

combootactinsmyosinmotor proteins
filopodia
-

Wound fluid Cinches #

branched
macrophages migrating towards bacterial Proteins resident actinfilamenthymyosiritmotorproteins

Wkkosslinkinothaptotaxis
.
-

helpsmore.microfitamentagainstanotherm.co
cells moveupagradienttowardattractiretaaortooundtoasurface filament
.
.

"
paonpgllmipeggia Proteinsonsurtaceot connectivetissue
-

Tlheadmilling
epithelial
migrating inwoundbed cell Phagocytosis extensions
.

Cell Migration wound healing 's metastasis Stable


.
.

Cellsmoveupagradienttowardshigherconc
.

resselwalkthrafonnectivetissuemovementriaml.ro SARCOMERE -

muscle contraction

migrating eachother
bundleofunits-inskele.to/musae-myosinIslidesactinacRoss
.

malignant
metastasis cells beyond tumor
.
.
-

thru connective tissue


-

thruresselwahto circulation
-

filaments
polymerization otactin
-
treadmill ing

depolymerization removing actinmonomersatlmnusenas


result -

@ cell
I

tubulin based Mort MICROTUBULE : Neurons


.

MICROTUBULES -

Within cells
protein synthesis ONLY in the cell body -

requires proteins at synapses


-

membrane extension Mttoundattoends -

Often minor butimpcomponentotameboidmrt


-
terminated 's dendrites
,

separation
chromosome
atmidlinegdepoly
I
regs coordinated polymerization
transport through axons } dendrites
.

atpol
w/o intact microtubules we can 't
taxoleffelfonspindk → Stops mitosis organelles secretory
-

, move or
-

Organelle Mort . -

using dynein } kinesin -

Providing intra Vesicles

important
.

.
motility

Cilia } flagella MAPS are


.

-0

relative Stability two transport cdyneinsskinesins ) allowing direction

n40c.am/dayCsomeaxonsare.1mIong7-CellsintheiRlnV.lr
way
-
- -

.

membrane extensions , mitotic
spindles are transient

Organelle MVTWIMAPS
-

phosphotautin alzheimers - MT instability → d axon


flagella } cilia are stable

transport of NT → I Neuron function


MAPS microtubule associated protein
motor protein
°
- -

MT : In the environment
forms bridge between microtubules organelle
-

cilia 's flagella :


specialized membrane extensions
motor protein requires ATP
.

relatively stable Reofmt


.

the only
motors in ONE Way
'

move

cilia fluid Mut over cell surface :


respiratory
. -

epithelial Cell
dynein -0
)
's -

move → interior
Ccellmevrehsbircaensei
.

flagella -

mort propels cell


through fluid 's sperm cel
kinesin -

⑤ move → cell edge ( receptors , transmitters


-

Cilia -

new drug target ?


multiple versions of motors encoded by separate
'

genes there are taste


receptors compounds
.

for bitter found on

Alice →

Chemical experiments
.

response

cells bitter Tfa


'Dintracellular
-

exposed to compounds -
>

Tciliary beating

possible target for cystic fibrosis !


'

new

cilia
clearing mucous
-
cell Adhesion
? variability in number z Size of JC
.

What holds tissues together


-
.

cell -

cell i cell substrate interactions


-

drug delivery challenge :


many drugs are

TOO big OR
hydrophilic
Mostly cellular I muscle ) w/ acellular I bone ,
-

tissues
transmembrane Ce REPORT loosens the
junctions of BBB
.

the
Junction components
Tdruo delivery
cell membrane
-

creating tissue homeostasis


proteins
-

the
breakage of JC → brain edema Cfheidaceumul )
'

cytoskeletal proteins
-

BBB
TIGHT Junctions : Location
Junction Types TAG
TJ -

btwn membrane epithelium ) blood vessel endothelial cells

tight junctions
-

help
" "

in Surround
"

separate vs out lumen tissue


"

.

gut v. .
.

anchoring junctions
-
'

Stops lateral diffusion in meohb .

gap communicating junctions


-

or
specialization in membrane
junctional complexes
TJ Occluding Claud in proteins form seal cells Snm
.

a a -

,
.

diff .

junctions colonize
apart ' TJ Proteins indirect contact → trans memes .
prot
May include links to
Cytoskeletal proteins
'

TJ function loss in disease -

helicobacter pylori
to increase mechanical integrity
forms peptic ulcers caused by the bacteria int
Junctional Completes Why should
.

I care ?
W/ the tight junction protein ; breaking the barrier
Blood Brain Barrier
causing acid from surrounding env .
to degrade tissue -

Junctions between cerebral microvascular endothelial cells


-

epithelial dysplasia
.

Blood brain barrier


rapid degradation →
cell damage →
cell replications

tight junctions restrict passage


-

Dna mutations g gastric carcinomas


-

adherens ( anchoring junctions AD Anchoring Junctions

Stabilize cell -

cell interaction
found in tissues
many

consequences
.

'
3
made of integrins C Tm proteins 3

Cytoskeleton
-
restricts passage of molecules
VS . TJ -
C Transmembrane )

plant toxins , poisons , amino acids , glucose ,


Two classes of AS

etc
adherens junctions L )
.

MF
-

actin

Of tissue
transport out blood to
surrounding
-

desmo some junctions


-

intermediate f -

keratin in skin

partly dependent
endothelial
"

porter system
"
on on

cells

limited compounds cross junctions


-

e 400mW & lipid soluble can


-

or cross

400 L
hydrophilic )
> & most soluble
H2O
.

are blocked
Anchoring Junctions
GAP Junctions -

communication

Integrins : CTM Prot )


Connex on proteins
-

channels joining cytoplasm

outside
off
Physical 3 fnctnl link btwn } the cell
creating
.

2- 4 nm se par .

A B dimers
'

z
the channel opens Klose s in response to

fun Ct : cell -
cell cell matrix in t

blood "
hi Ca
-

hi Ht pH )
,
(
.

, low →
SHUT

Clotting cell
migration low cat low Ht OPEN
,

high pH MW must
-
-

regulation Of integrin function


bee 1000mW
. .

phosphorylation on Cy top tail


electrical signals in heart
.

integrins allow for cell retraction for


intercalated disk :
gap junctions ,

Mvt CMF )
moving along length Of Cell malfunction →
.

Tin migration thru ECM → WBC infill


arrhythmia
cancer cell spread for heart contraction : we want Connex ons to

integrins 's Motility be Open Ht


"
,
10 ,
loca
'
"

surface
'

WBC roll along inner of intact bv .

Epithelial Cells secrete haptotactic molecules ,


which

integrins interact w/ on the lumen side

causing :

Integrin transfer of signal → inside cell

cytoskeleton for
protrusion § migration of WBC

across the vessel wall C treadmill ing )

Integrins Dysfunction -
the patients the transom . protein

Nate
healthy low PAR
-

, su

Nick →
kidney failure high su PAR

SUPA R shape of cell


change memb .
extension by

integrin , disrupting kidney filtration , causing large

to secreted w/ urine
proteins be

Soluble hero kinase plasminogen Activator Recept

Su DAR
Lecture
3456

Protrusion , Attachment Retraction


on PARWKEH
migration
Protrusion extension .

actin polymerization atleadingedgeotmembrane-tamellipod.la 's filopodia


Attachment Adhesion Plaques .

.
-

focal contact -

directcont.lu/environment-StresSfibersmadeupof
microfilaments filamentous actin -

interaction sitewltransmemb .

integrin protein dimers

* vinculinttalin connect The connection wladhesionplaaues


- -


helpmakedirectcontactwtthe environment
Retraction : release
adhesion plague disassembly
-

Intracellremoralottheadhesionplaguetromitstrailingends
Microfilaments -

Mvt

Transient Structure contractile Rings


.

incytokinesistateincelldivisionllytokinesis)
.

combootactinsmyosinmotor proteins
-

cinches # ecelbinthemiddleotthecell

resident -

actinfilamenthymyosinimotorproteins.nl/psmore.MicRofi
lament against another microfilaments
Tlheadmilling
Phagocytosis extensions
Stable
SARCOMERE -

muscle contraction

eachother
Actinsbisease
Actin mediates internalization 's release of some viruses M4ROHbU Accessory Proteins maps -

HNbuddingpropelkdbyall.nl/ongationc polymerization) rmotorproteins-kinesinsgdynel.ms


?
could Actinbeconsidereda therapeutic antiviral target otau proteins
-
.

assembly
facilitate 's
of
control
Stability Microtubules
cytochalasin -

inhibits actin polymerization I elongation) -


,

}
blocks addition otnewmonomerstoactin filaments excess tall collapses MT'S

:fII
-

:&
III
:c
!
-

phosphorylation
hesitations
finger
:&
:{
"
.mil:9?nsmheErEaEionna
tuna .

.am/-sererinoenzymeDiameteR:n25nmlwidesH
bundleofunits-inskele.to/musae-myosinIslidesactinacRoss
Microtubules .it#IgY.at:i:;:awaumpsinanniimersaiseaseaisrums.
membranesupport to synapse
transporter .

Characteristics : Mltxcessoryproteins

Polarity
Stability dynamic easily assembled
-

katana

healthy cells
amtsinaucells-sorganelleswmotorp.ro
Occurrence differing teinsstransport :
louweatfehomf
.tt#f-afifYeuitastewkatanin
TYPES Morenegends more depolymerization
normal turnorerotmtnetwo
tubulin ( alternate in polymer)
's

LIB
-

polymerization dependent onmgztg,GTp


.

-7

:
⑤ endaddingioendremoringiadditionattoendpushes membrane forward initphkohslihfffhf
.fr#hitsxskataninhikataninsXSM-
depolymerization

hiphosphotiauiformspairedheliealtilamentsthatare diagnosticof disease


lossotimttphos-tautilamentsimpairau.nu transport of proteins needed @ syn .

forsignaling
Lecture 3.4.56
Microtubules Tubulin based Mort -

F- Tubulin Targeting DRUGS


within cells
Clinical lmpactofcytoskeleton
.

membrane extension Mttoundattoends -

often minor butimpcomponentotameboidmrt


-

,
i

l49ootcancerclinl.ca/tRialdruostargettubUlin
-

separation
chromosome
latmidlinetsdepoly
regs coordinated polymerization
-

Taxol l ) isananticancerdruo
atpol
-
taxoletfectonspindk → Stops mitosis inhibits →
by bindings Stabilizes MT
-

Organelle Mort . -

using dynein 's kinesin -

Providing intra
Polymer Taxlplol
.

cellsintheirlnv.ir motility
-

-
.

.
Cilla 's flagella Natural Source -

Taxus brevifolia -
Pacific Yewtree -

uses

paclitaxel
-

relative Stability →
membrane extensions , mitotic
>
Golbsotbarkfortchemopt .
-
semisynthetecesnowmade
spindles are transient

depolymerization
Organelle MVTWIMAPS tubulin tubulinisinhibitedinchromosome separation
.

flagella cilia
-

} are stable .

MAPS microtubule associated Protein Used FOR disease breast 's ovarian cancer
motor protein
. -
- -

forms bridge between microtubules organelle blocking later steps of chromosome separation

motor protein requires ATP thcissueisthatitblockschromosomesep.in healthy

the only
Cells
motors in ONE Way
'

move

dynein -0
) Cokechineitgcolcemid
's
.

move -s interior
Cceumqrensbigqense ,

kinesin -

⑤ move → cell edge ( receptors , transmitters


-

binds monomer of tubulin -


prevents polymerization

multiple encoded natural source Colchicum autumnal e C Autumn


-

versions of motors by separate


'

genes Crocus )
disease use
goutcuricacvd buildup
-

important
MICROTUBULE : Neurons
causing inflammation w/ WBC infiltration )

protein synthesis ONLY in the cell body -

requires proteins atsynaps.es decreases MVTOFWBCTO Goto cells w/

I terminated } dendrites buildup Of uric acid


n40c.am/dayCsomeaxonsare.1mlong7
through
.

transport axons } dendrites issue : wound 's can 't heal


properly
w/o intact microtubules we can 't Preclinical Findings -

cancer Ctaxol )
organelles secretory
-

, move or

Vesicles Alzheimer 's Disease Neurodegenerative tauopathy


'

MAPS theres too much pp causing MT destabilization


.

are Tau
.
- -

-0

two ) allowing direction mouse Model wlhypslrpp
'

way transport cdyneinsskinesins tale


- -
-

phosphotautin alzheimers - MT instability →


taxon MUSTUSEADRUG that is small - BBB →
Epob

transport of NT - tr Neuron function Results OTEPOD

Mtiinthe environment increased MT integrity dpptau


'

cilia 's flagella specialized membrane extensions reduced axonal dystrophy


-

:
-

relatively stable Reofmt improved atonal transport


.

cilia fluid mvtovercell surface :


respiratory improved cognitive effects
. -

epithelial
'

cell

flagella Mort propels through fluid


nodose limiting side effects
cell cel
-

sperm
.

;
.

Cilia newdruotarget ? FPOD Clinical Testing ?


-
-
-

there are taste


receptors compounds Tubulin Targeting DRUGS Vinblastine Vincristine
}
.

for bitter found on :

Alice Stops aggregates w/ monomer


.

Madagascar periwinkle
-

Chemical experiments common


.
-

response
-

cells exposed to bitter compounds -


Tccaittintraceuular >
disease use -

hodkins disease , lymphocytic

Tciliary beating lymphoma

possible cystic fibrosis !


Stops mitotic spindleformatioh
.

target for
'

new


cilia
clearing mucous stops polymerization -
healthy cells
-

need Chromosomes fordivision


Lecture 3456 cont .

Intermediate Filaments -
cell -

cell
junction
Characteristics :

Stability elative static


-

ly

Diameter intermediate no
'

, nm

Occur Ce subject mechanical stress


long
distances Skin } Nerves
-

en -

cells to or →

Subclasses keratin slain hair nails epithelia ) vimentincfibrobcasts )


'

,
,
, ,

neuro filaments l neurons ) g nuclear lamina -

directly under skin

envelope all Cells w/ nucleus


-

polarity no polarity add I subtract on either end


-
.

.

Structural
Functional Role :

most IF as filaments ,
little monomer

polymer is stable to provide mech strength


'

When do IFS need to be disassembled ?

mitosis 3 cytokinesis for chromosomal separation }

cytoplasmic division
by phosphorylation dephosphorylation
cell attachment to environment
.

Stability adds resilient , longterm connections

'

Cell -

substrate attachments -

hemidesmosomes

Cell cell attachment de SMO Somes


.
- -

Genetic Disease -

IF dysfunction

EBS epidermal ysis Bull Osa Simplex


-

Skin blisters formed by stress caused by mutant


.

keratin → IF is weakened , causing blisters

cell Adhesion
?
.

What holds tissues together


cell -

cell i cell substrate interactions


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NE W S

FEATURES
OMEN IN THE
BLOOD
A protein marker
predicts health crises—
but can it cause them?

By Stephen S. Hall

N
ick Henry first experienced the

Downloaded from http://science.sciencemag.org/ on May 4, 2018


symptoms of kidney disease in
2004, shortly after the 19-year-
old had a severe reaction to a
spider bite. “I woke up one morn-
ing, and I was just swollen from
head to toe,” he recalls. But doc-
tors managed Henry’s disease,
allowing him to return to his un-
usually active lifestyle—including baseball,
softball, basketball, flag football, golf, and
fishing—in his northeast Louisiana home-
town of West Monroe. Shortly after he wit-
nessed the death of his mother in a motor
scooter accident in 2012, however, Henry’s
renal health took a dramatic turn for the
worse. “It’s almost as if my body went into
shock,” he says. “Within a couple months,
boom, I started swelling up again.”
That swelling was a sign that his kidneys
were no longer working normally. A biopsy
confirmed that he had focal segmental glomer-
ulosclerosis (FSGS), a severe form of kidney
disease. In FSGS, the kidney’s glomeruli—the
microscopic filtration units that sieve excess
fluid and waste products from the blood—
become overly leaky; essential proteins such
as albumin seep out, disrupting blood chem-
istry and causing fluid to leak from the blood
vessels into tissues throughout the body.
Henry’s condition deteriorated so rapidly
that by July 2014, his doctors in Shreveport,
Louisiana, decided to remove both diseased
kidneys. The next month, Henry received a
transplanted kidney from his identical twin,
Nate, who was healthy, even though FSGS
can be genetic in origin.
Within a day of the transplant, however,
Henry felt like the swelling was coming
PHOTO: KEVIN BEASLEY

back. At first, his doctors reassured him that

Nick Henry had a kidney transplant,


but his new organ quickly deteriorated,
and he spends his nights on dialysis.

254 sciencemag.org SCIENCE

Published by AAAS
NEWS

he was doing fine. “Once they checked my factors have been high blood pressure, diabe- “What is inflammation?” asks biochemist
urine, saw me spilling a bunch of protein tes, and African-American ancestry. (Several Jesper Eugen-Olsen of the University of
again,” he says, “they realized [FSGS] was mutations associated with increased risk are Copenhagen, a pioneer in suPAR research.
attacking the new kidney.” Three days after more common in African-Americans.) “It’s the language of cells. It’s how cells com-
the surgery, Henry’s doctors conceded that But research by Reiser and others has municate with each other. When something
the newly transplanted kidney had already dramatically challenged that traditional is going wrong, the immune system is acti-
become diseased. His transplant doctor, picture of risk. If suPAR levels are low, vated. It produces suPAR … and suPAR is a
Neeraj Singh of Louisiana State University people with the high-risk genes are no more voice that just shouts, ‘Get on with it! Some-
in Shreveport, says the recurrence was “one likely to develop kidney disease than people thing is going on!’”
of the most dramatic cases I’ve seen.” without those gene variants, Reiser says. If
The sudden failure of Henry’s new kidney suPAR levels are high, people are at greater IN NEITHER BACKGROUND nor appearance
is a recent chapter in a long-running medical risk of developing the disease regardless of does Reiser conform with the public im-
mystery, dating to when kidney transplants whether they have the mutations. age of the director of a major metropoli-
became routine in the 1970s. Up to 30% of Molecular studies in animals as well as tan medical center. His 10th floor office at
transplanted kidneys fail in FSGS patients— a growing number of analyses of large hu- Rush sits just behind a corridor lined with
not because of immune rejection by the body, man populations associating suPAR with photographs of hospital administrators go-
as doctors first suspected, but because the kidney disease have bolstered his confi- ing back to the 19th century—stern-faced,
new organ immediately begins succumbing dence—and convinced him the disease all-knowing medical patriarchs. Inside,
to the same disease process that ravaged the could be treated by suppressing suPAR. Reiser, 46, sports a stylish striped blue suit,
original ones. As he struggled to
cope with that devastating turn

Downloaded from http://science.sciencemag.org/ on May 4, 2018


of events (and relied on dialysis
to stay alive), Henry traveled to
Chicago, Illinois, to consult with
Jochen Reiser, a kidney disease
specialist who is chairperson of
internal medicine at Rush Uni-
versity Medical Center there.
Ever since he learned about
such transplant failures 2 de-
cades earlier, Reiser has been
convinced that “there is some-
thing in the blood circulating
that attacks the kidney. And we
were out to catch that.” What
he and colleagues claim to have
“caught,” in an elegant but still
unfolding story of molecular
detective work over the past
10 years, is a protein known as
soluble urokinase plasmino-
gen activator receptor (suPAR).
When Reiser analyzed blood
samples from the Henry twins,
the results aligned with the
message he has been preaching
with evangelical fervor for years.
Nate, the healthy brother, had Nate Henry (right), Nick’s identical twin, is healthy. Nick’s high levels of a molecule called suPAR may explain his illness.
relatively low levels of suPAR;
Nick’s were high—a driving force, Reiser be- Some other researchers aren’t convinced, fashionably stubby beard, red socks, and
lieves, of his kidney failure. noting that several clinical studies found slick dark hair. Known among colleagues
Chronic kidney disease affects 14% of the no clear association between suPAR levels as ambitious and scientifically gregarious,
U.S. population, with estimates suggesting and FSGS. But on both sides of the de- he has been eager to collaborate with any-
nearly 600 million people affected world- bate there is widespread fascination with one interested in exploring suPAR biology,
wide. The disease steadily erodes the kid- suPAR, a ubiquitous, Zelig-like bystander and his brash, full-on style extends to the
neys’ ability to filter the blood, often leading molecule that, at elevated levels in the conspicuous display of large-format books
to cardiovascular disease and premature blood, seems to presage many health ca- celebrating the history of Aston Martins (he
death. Kidney disease—which can directly lamities, such as heart attacks, diabetes, owns one) and Porsches on the coffee table
attack the filtration process, as in FSGS, or and premature death. Whatever suPAR’s in his office. Describing the speed of data
PHOTO: KEVIN BEASLEY

damage the kidney’s support structure—is precise role in kidney disease, the molecule collection for a paper that several years ago
particularly insidious because by the time appears to be a potent signal broadcast by ended up in The New England Journal of
the first diagnostic signs appear, patients an immune system under siege. It is exqui- Medicine (NEJM), he says, “It was like going
have irreversibly “burned off” much of their sitely sensitive to inflammation, an accel- from zero to 200 in no time,” adding sheep-
kidney function. Historically, the leading risk erant for many diseases. ishly, “Car analogy.”

SCIENCE sciencemag.org 20 APRIL 2018 • VOL 360 ISSUE 6386 255


Published by AAAS
NEWS | F E AT U R E S

Born and raised in the small German vil- losing them, there’s a point of no return. … kidney disease, suPAR levels were already
lage of Remchingen, on the eastern edge You are basically walking toward end-stage high and offered no prognostic value. With
of the Black Forest, Reiser got his medical renal disease.” Reiser claiming to have found the “holy
degree and Ph.D. from Heidelberg Univer- What causes such damage? Reiser sus- grail” even as several groups were reporting
sity and did an overseas residency at Albert pected that the mysterious blood-borne discordant results, says one source, “People
Einstein College of Medicine in New York factor disrupts podocytes through receptor felt very emotional.”
City. Specializing in kidney disease, he went molecules on their cell surface. He focused
on to conduct research at Harvard Medi- on one: b3-integrin, a molecule whose ac- BY THAT POINT, another key strand of the su-
cal School in Boston and became chief of tivation perturbs the shape and motility PAR story had emerged in Europe. There,
nephrology at the University of Miami of cells. When he looked for the molecular the focus was on the molecule as a potential
Leonard M. Miller School of Medicine in key that turned the lock of the integrin re- biomarker for a range of diseases.
Florida before being hired by Rush in 2012. ceptor, he discovered that oncologists had The first clues came from AIDS patients. In
Reiser’s arrival in the United States in already been working on one such protein, Copenhagen, Eugen-Olsen and others exam-
1999 coincided with renewed interest in urokinase PAR (uPAR), a cell surface recep- ined blood collected from more than 300 HIV
solving the mystery of why up to 30% of tor that plays a role in cancer metastasis. patients in the early 1990s, before life-saving
FSGS patients who receive transplants Reiser became even more intrigued when antiretroviral therapies became available. All
see the disease recur in the new kidney. he learned that uPAR can be cleaved from those patients had died, but a retrospective
Just 3 years earlier, a group headed by cell surfaces and circulate in the blood—at analysis showed their suPAR levels eerily
Flavio Vincenti, a transplant specialist at which point it becomes a soluble cousin correlated with disease progression: Higher
the University of California, San levels were associated with an earlier
Francisco (UCSF), and Virginia Savin, death. Eugen-Olsen then spent several

Downloaded from http://science.sciencemag.org/ on May 4, 2018


at the Medical College of Wisconsin years collaborating with a hospital in
in Milwaukee, announced a major “The data gets stronger and stronger the West African nation of Guinea-
clue. They reported in NEJM that that suPAR is the worst toxin you can Bissau, testing suPAR levels in pa-
they had amassed evidence for an tients suspected of being HIV-infected.
FSGS-promoting factor in the blood have for the kidneys.” Again, higher suPAR levels predicted
of transplant recipients who’d expe- Jochen Reiser, Rush University Medical Center a quicker death among the infected.
rienced recurrences; they couldn’t Surprisingly, however, suPAR also pre-
isolate the exact protein, but when dicted mortality in patients who didn’t
colleagues later injected an extract of such known as suPAR. Maybe suPAR was the have AIDS; many turned out to have tuber-
patients’ blood into rodents, the animals’ mysterious kidney-destroying factor. culosis. That finding led him to hypothesize
kidneys became permeable and spilled pro- In 2011, Reiser and colleagues reported in that suPAR might be a more general bio-
tein in the urine. That mysterious “perme- Nature Medicine that in cell culture, suPAR marker for chronic inflammation.
ability factor” became “the holy grail” of the damaged human podocytes through the In 2001, Eugen-Olsen founded the com-
field, according to Sanja Sever, a molecular integrin pathway. The researchers supple- pany ViroGates, which began to manufac-
biologist who studies kidney disease at Mas- mented that evidence with three mouse ture a relatively inexpensive test to measure
sachusetts General Hospital in Boston. models showing that rodents with elevated suPAR levels in the blood. With the test in
While still in Germany, Reiser had levels of suPAR suffered kidney damage, hand, he and colleagues in Copenhagen be-
trained his research efforts on a unique although sometimes more slowly than in gan to look at collections of blood samples
renal cell called the podocyte (so named FSGS. With human clinical data suggest- banked in large-cohort prospective studies.
because of its amoebic, faintly footlike ing that elevated suPAR levels correlated In one called MONICA, which monitored
extensions). That choice turned out to be with the recurrence of FSGS in patients, a healthy members of the Danish population
fortunate. The kidney has about 1 mil- picture emerged in which the protein trig- for about 13 years, elevated levels of suPAR
lion glomeruli, and in each one, hundreds gers a pathogenic process that ultimately were associated with a higher risk of cardio-
of podocytes bridge the gap between the produces holes in the coffee filter, leading vascular disease, type 2 diabetes, cancer, and
bloodstream and the urinary system. to kidney disease. premature death. Two other large European
Their footlike extensions wrap around The findings both electrified and polar- populations, enrolled in the Malmo Diet and
capillaries snaking through the kidneys ized the nephrology community. In a com- Cancer Study and the Danish Inter99 Study,
and, along with two other layers of tissue, mentary for Nature Medicine, Martin Pollak showed similar associations.
form a physical mesh of cells, like a three- of Harvard Medical School, who studies the The findings caught the attention of re-
ply screen door, that allows only small genetics of kidney disease, and nephrologist searchers at Emory University School of
molecules—sodium ions, potassium ions, Stuart Shankland of the University of Wash- Medicine in Atlanta who had been looking
and metabolic wastes—to pass into the ington in Seattle described the findings as for new and better biomarkers to predict
urinary tract. When the podocytes become “paradigm shifting for our understanding risk of adverse cardiac events in people with
damaged, however, they essentially lose of the pathogenesis of FSGS.” heart disease. The researchers had built the
their architectural integrity. The kidney fil- But some groups could not find the same Emory Cardiovascular Biobank with serum
ters then become leaky, allowing larger es- clinical association between suPAR levels from several thousand patients. “We draw
sential proteins such as albumin to escape and recurrent disease in FSGS patients, and blood, and we follow them for years,” says
from the blood and pass into the urine. other groups questioned the protocol and Salim Hayek, a physician and research fel-
It’s like a coffee filter, Sever says. “If interpretation of the animal models. And re- low at Emory. When two of Hayek’s col-
there are holes in your filter, then you gardless of whether suPAR actually destroys leagues, Danny Eapen and Arshed Quyyumi,
get some coffee grounds in your urine.” the kidney, many nephrologists thought its delved into the biobank, they found that
Podocyte damage can be reversed early in levels were not very informative—by the higher suPAR levels predicted heart attacks
kidney disease. But, she says, “If you keep time those specialists saw patients with and death, as they reported in the Journal

256 20 APRIL 2018 • VOL 360 ISSUE 6386 sciencemag.org SCIENCE

Published by AAAS
of the American Heart Association in 2014. An organ under attack
(At the annual meeting of the American In one scenario for a severe form of kidney disease, a blood-borne molecule called soluble urokinase
College of Cardiology last month, Hayek plasminogen activator receptor (suPAR) disrupts the organ’s filtration units, or glomeruli,
presented further evidence from the Emory which remove waste and fluid from the bloodstream. Other molecules may intensify this attack.
group, suggesting that suPAR is a better
predictor of cardiac events including heart Monocyte Immature A dangerous immune response
attacks and death than any other biomarker Neutrophil myeloid cell Animal models suggest immature
in widespread clinical use.) immune cells in the bone marrow release
In addition to serving as an omen of ill more suPAR when an organism is
under attack. The molecule, an all-purpose
health, suPAR seems to be a remarkably
Bone marker of ill health, may be directly
sensitive indicator of lifestyle insults. Stud- suPAR toxic to the kidney.
marrow
ies have shown that the protein’s blood
levels typically rise with obesity and with
smoking. (Eugen-Olsen, an inveterate
smoker, confesses that he quits when his su-
PAR levels rise and resumes when they sub- Kidney
side again.) “Just looking at the data,” Hayek
says, “clearly the environment is a much
larger contributor to suPAR than genetics.” Glomerulus
With its links to multiple diseases and en- Functional unit
vironmental stresses, suPAR appears to sit of kidney

Downloaded from http://science.sciencemag.org/ on May 4, 2018


at the nexus of immune signaling, chronic
inflammation, and tissue damage. Among
the protein’s normal sources are fat cells,
immune cells, and endothelial cells, which
produce low baseline levels. But a team led
by Reiser and David Scadden of the Harvard Podocyte
Stem Cell Institute showed in 2017 that in
mice, immature “stemlike” cells in the bone
marrow can release a pulse of suPAR when
the immune system detects an attack.
Reiser believes suPAR is an ancient and
unspecific way for the immune system
to send urgent signals to the major organ
systems when an organism faces a severe
challenge from disease or the environment. Podocyte lost to
Kidney damage, he says, is the long-term urinary space

cost of that vital signaling mechanism. “As


one example,” he says, “you get infected, you
release more suPAR, you open your kidneys
up, and you can dump the big molecules out A HEALTHY FILTER KIDNEY DISEASE
into the urine. Almost like a primitive cou- In each glomerulus, the footlike extensions of cells By binding to b3-integrin, a surface receptor
pling of the immune system to vital organs.” called podocytes wrap around capillaries, fitting on the podocyte feet, suPAR is thought to change
In an acute infection, he says, the body ur- together tightly to create narrow “slit diaphragms.” The their shape, disrupting the kidney’s filter. That
gently needs to flush out bacterial toxins, slits form a fine mesh that allows only small molecules allows large proteins such as albumin to leak into
to escape from the bloodstream into the urine. the urine—a sign of kidney disease.
relatively big molecules. But if that inflam-
matory signaling becomes chronic, it takes
its toll on kidney function—a trade-off that
may have been acceptable earlier in human Slit diaphragm Albumin leakage
history, Reiser suggests, but is less so now.
“If you live 40 years long, you can burn off
the kidney this way, no problem,” he says.
“If you live to be 80, 90, 100, you might burn
off your kidneys too soon.”
For Reiser, the Emory cardiac biobank
offered a chance to put to rest the notion
that high levels of suPAR are simply a non-
GRAPHIC: V. ALTOUNIAN/SCIENCE

specific sign of failing kidneys, not a cause.


When he saw the 2014 heart risk paper
from the Emory group, he had the obvious
question: Could the large databank show b3-integrin
whether suPAR levels predicted the onset of Glomerular basement
kidney disease years later? He immediately membrane
Capillary suPAR
fired off an email to Hayek. Endothelial cell

SCIENCE sciencemag.org 20 APRIL 2018 • VOL 360 ISSUE 6386 257


Published by AAAS
NE W S | F E AT U R E S

The Emory-based group quickly agreed University School of Medicine in Balti- plicated” than the initial findings in 2011 sug-
to conduct follow-up renal examinations in more, Maryland, to compare the influence gested, Reiser concedes. “But meanwhile, the
more than 1300 patients who had no evi- of suPAR and two gene mutations known data gets stronger and stronger that suPAR is
dence of kidney dysfunction when they en- to predispose African-Americans to kidney the worst toxin you can have for the kidneys.”
rolled. The team found a strong link between disease. A study of about 600 participants The controversy may not be resolved to
high suPAR levels and the later development revealed that if suPAR levels remain low, everyone’s satisfaction until a human trial
of kidney disease. For patients with the high- “no notable differences” in kidney dys- indisputably shows that removing suPAR
est levels of suPAR, the risk was three times function were apparent between people cures or slows the progression of kidney
that of patients in the lowest group, and su- who had the high-risk “disease genes” and disease. Several groups are trying to develop
PAR levels could predict kidney disease up to people who did not. Conversely, high levels a monoclonal antibody drug that would
5 years before the first symptoms appeared. of suPAR strongly predicted kidney disease remove suPAR from the blood. One such
“The effect was huge,” Hayek recalls. in African-Americans, regardless of whether group is Trisaq, a company Reiser and Sever
The association was so robust, he says, the individual had the genetic variants. founded in 2011. Vincenti said his group also
that when the group first submitted its has developed monoclonal antibodies to su-
findings for publication, “the first response YET NEPHROLOGISTS are still divided PAR for clinical testing. “I was excited to try
we got from [NEJM] was: ‘How is that as- about whether suPAR actually attacks the it in patients,” he says. “But we could not
sociation so strong? Is that real? Something kidneys—and if so, how aggressively. Doubt- demonstrate, at least in our samples, that
is wrong with your cohort.’” But after Hayek ers point to the conflicting clinical results suPAR was a biomarker for either FSGS or
and Reiser found the same association in and the slow progress of kidney damage in recurrent FSGS. [That’s] held it back.”
The first human proof may come not from
a drug, but from a medical device. Miltenyi

Downloaded from http://science.sciencemag.org/ on May 4, 2018


Biotec, a company in Bergisch Gladbach,
Germany, makes apheresis devices, which
remove substances from plasma, and it is
developing a technology that would selec-
tively scrub suPAR out of patients’ blood.
“The key question,” notes CEO Stefan
Miltenyi, “is if suPAR is the cause [of ] re-
nal diseases or just a bystander molecule.”
Miltenyi hopes to launch a clinical trial
in 2019.
For FSGS patients such as Henry, who re-
lies on 8-hour overnight sessions of dialysis
to stay alive, a breakthrough therapy can’t
come soon enough. But suPAR is already be-
ginning to influence clinical decisions. Singh,
Henry’s transplant physician, has used su-
PAR levels to manage the care of several kid-
ney patients. And since 2013, every patient
arriving at the emergency department at Co-
penhagen University Hospital Hvidovre has
undergone suPAR testing to help physicians
make triage and discharge decisions.

REISER OFTEN LIKENS suPAR to cholesterol—


a key marker and disease-associated mol-
ecule that can be monitored and, perhaps,
Jochen Reiser has spent years amassing evidence that suPAR mounts a powerful assault on the kidney. ultimately controlled. But the main lesson
of suPAR, he believes, is cautionary in an
a second, unrelated cohort—the Women’s Reiser’s mice with elevated suPAR levels. age of genomics and personalized medicine.
Interagency HIV Study—NEJM published The original 2011 animal and clinical data Although a huge amount of attention (and
their findings in 2015. “In that paper,” are “as complete as you can get,” Vincenti government coin) has been devoted to iden-
Reiser says, “we could show that suPAR is says. “But at some point, there has to be in- tifying genes associated with disease, the
the strongest risk factor known in healthy dependent duplication of that data.” environment can sometimes trump them. “I
people for new chronic kidney disease. Several unresolved issues might explain think that the gene adds to the risk profile—
Even stronger than hypertension, diabetes, the discrepancies. Different forms of suPAR it’s part of the picture,” he concedes. “But
PHOTO: RUSH PRODUCTION GROUP

black race—all of these risk factors that are can circulate in the blood, and some vari- the environment is a way-underestimated
known to be strong. When you adjust for ants might be more pathogenic than whole modifier that becomes way more important,
those, suPAR had the strongest risk.” suPAR. And a team led by Minnie Sarwal of quite frankly, than the underlying gene
In the latest piece of evidence, published UCSF, Dany Anglicheau of Necker Hospital event. And this is … a beautiful illustration
last summer in Nature Medicine, Reiser in Paris, and Reiser has shown that in FSGS, of exactly that principle.” j
collaborated with researchers at the Af- a second blood-borne factor, an anti-CD40
rican American Study of Kidney Disease autoantibody, works with suPAR to attack Stephen S. Hall is a science journalist in
and Hypertension, based at Johns Hopkins podocytes. “Everyone agrees it’s more com- New York City.

258 20 APRIL 2018 • VOL 360 ISSUE 6386 sciencemag.org SCIENCE

Published by AAAS
to speculate that such a broadly represented NEUROSCIENCE
population contains further subsets of spe-
cialized fibroblasts. Furthermore, it is not
entirely clear how this large population orig-
inates from a very small pool of precursors
Systemically treating spinal
in skin at early embryonic time points, nor
where other fibroblast-type, mesenchymal
cord injury
cell subsets fit into their lineage partition,
such as hair follicle–associated dermal pa- A drug that crosses the blood-brain barrier has therapeutic
pilla and sheath cells and vascular smooth potential for central nervous system trauma
muscle cells. In addition, the results of this
study focus primarily on the fibrogenic ac-
tivity of En1-lineage–positive cells, leaving By Amanda P. Tran and Jerry Silver stabilizes microtubule polymers and pro-
us to wonder about the origins and purpose tects them from disassembly. Suppression

S
of the lineage-negative cells that constitute pinal cord injury is a debilitating con- of microtubule dynamics thus interferes
at least 30% of adult skin fibroblasts. dition. Axons of nerve cells are sev- with cellular processes such as cell divi-
Finally, the authors used a cell surface ered, resulting in a range of deficits, sion and cell motility. Indeed, it was shown
marker screen to identify CD26/Dpp4 as a including the loss of voluntary move- that caged Taxol (which could be activated

Downloaded from www.sciencemag.org on May 15, 2015


unique label for En1 fate-mapped fibrogenic ments and sensation. Failure of axonal in a restricted area) specifically stabilized
fibroblasts in adult skin. Subsequent experi- regeneration after such an injury may the dystrophic growth cone microtubule
ments revealed that prospectively isolated be partly explained by a decreased intrinsic cytoskeleton in cultured rat neurons, and
adult CD26+ mesenchymal cells primar- capacity for neuron growth, especially at the that this was sufficient for axon forma-
ily contributed ECM components during lesion site (1). On page 347 in this issue, Rus-
wound-healing and tumor response assays. chel et al. (2) show that this inhibition can be
More intriguingly, the authors observed a overcome with a small molecule that can be
slight but significant difference in fibrogenic injected into the body cavity, cross the blood- “…there are currently no
gene expression between CD26� and CD26 � brain barrier, and reach the central nervous
fibroblasts that was greatly exacerbated by system. The drug, epothilone B, stabilizes
drugs approved…to treat this
a wounding assay stimulus. Thus, although microtubules in extending axons, thereby traumatic injury that allow
fibroblasts from separate lineages are intrin- promoting spinal cord regeneration.
sically similar at baseline, they are unique Upon approaching the glial scar at the
for functional recovery.”
in their individual transcriptional and func- lesion site of the spinal cord, the tips of re-
tional responses to signals from within the generating axons form swollen dystrophic tion (9). This effect was reversed with no-
greater milieu of the skin. growth cones (3). These were first described codazole, a microtubule-destabilizing drug
Not only is CD26/Dpp4 useful for isolat- as “sterile clubs” by the neuroscientist and (8, 9). Intrathecal delivery (injection into
ing or identifying fibrogenic cells in situ, Nobel laureate Ramón y Cajal, who also be- the spinal fluid) of Taxol following a dorsal
but the discovery is also clinically relevant. lieved that they persisted only briefly in a hemisection of the rat spinal cord also pro-
Dpp4 signaling itself appears to coordinate quiescent state before the axon “died back” moted microtubule stabilization, allowing
fibrogenic activity, and the authors could to a sustaining collateral (now defined as a increased axonal penetration through the
mitigate scar size during healing by apply- branch off the main axon that feeds back glial scar (10). Taxol additionally decreased
ing a specific Dpp4 inhibitor to wound sites. onto the neuron’s cell body) (4). By con- the ability of transforming growth factor–
This discovery has far-reaching implications trast, Ruschel et al. describe how dystrophic β1 to adversely affect rearrangement of the
for drug development, provided the observa- growth cones remain in the injured human cytoskeleton in astrocytes, which reduced
tion proves relevant to wound healing in hu- spinal cord for a remarkable 42 years after scarring induced by spinal cord injury (10).
man skin as well. Furthermore, the utility of injury. Advances in in vivo imaging have Using a more clinically relevant microtu-
Dpp4 as a marker or druggable target might also revealed that, for a time, dystrophic bule stabilization strategy as a putative spi-
also be applicable to studying or treating fi- growth cones are dynamic and can regener- nal cord injury therapy, Ruschel et al. tested
brosis in organs outside of the skin. ■ ate in a more accommodating environment epothilone B in different rat models of spi-
RE FE RENCES
(5). Moreover, dystrophic growth cones nal cord injury. Epothilone B also targets
1. Y. Rinkevich et al., Science 348, aaa2151 (2015). eventually form synaptic-like relationships tubulin, but is a member of a different fam-
2. R. R. Driskell, F. M. Watt, Trends Cell Biol. 25, 92 (2015). with oligodendrocyte precursor cells in the ily of drugs. Unlike Taxol, it penetrates the
3. R. Sennett, M. Rendl, Semin. Cell Dev. Biol. 23, 917 (2012). lesion core, enabling them to persist for blood-brain barrier, as seen through mass
4. J. M. Sorrell, A. I. Caplan, J. Cell Sci. 117, 667 (2004).
5. R. R. Driskell et al., Nature 504, 277 (2013). long periods (6, 7). spectrometry analysis of rat spinal cord tis-
6. R. Atit et al., Dev. Biol. 296, 164 (2006). Electron micrographs of adult rats with sue after intraperitoneal delivery (injection
7. G. J. Spangrude et al., Science 241, 58 (1988). spinal cord injury illustrated that dys- into the body cavity). Ruschel et al. found
8. S. Werner et al., J. Invest. Dermatol. 127, 998 (2007).
9. S. Madar et al., Trends Mol. Med. 19, 447 (2013).
trophic growth cones are bloated with that by stabilizing microtubules, epothi-
10. B. O’Sullivan, W. Levin, Semin. Radiat. Oncol. 13, 274 (2003). disorganized microtubules arranged in lone B enhanced axon regeneration and
11. H. Y. Chang et al., Proc. Natl. Acad. Sci. U.S.A. 99, 12877 nonparallel networks (8). To better under- ultimately improved sensorimotor function
(2002).
stand the internal machinery of dystrophic in an injured rat, boosting intrinsic axo-
ACKNOWLEDGMENTS growth cones and determine whether they nal growth while reducing axon-inhibitory
R.S. was supported by NIH fellowship F30AR065847; M.R. are malleable, earlier studies assessed the scarring after injury.
by NIH grants R01AR059143; R01AR063151 and NYSTEM
(C029574).
effects of the anticancer drug paclitaxel
(Taxol). Paclitaxel belongs to the taxane Department of Neurosciences, Case Western Reserve
10.1126/science.aab0120 family of drugs that targets tubulin. It University, Cleveland, OH 44106, USA. E-mail: jxs10@case.edu

SCIENCE sciencemag.org 17 APRIL 2015 • VOL 348 ISSUE 6232 285


Published by AAAS
IN SIG HTS | P E R S P E C T I V E S

Without epothilone B
Fibroblasts

Lesion in dorsal spinal cord Microtubules in


Scarring dystrophic growth cone

With epothilone B

Dual acting drug. After spinal cord injury, dystrophic growth cones fill with disorganized microtubules and axons cannot extend. Fibroblasts migrate to the lesion and contribute
to an environment that inhibits axon outgrowth. Systematically delivered epothilone B, which crosses the blood-brain barrier, stabilizes neuron microtubules and promotes axon
extension through the injured site. It also hampers fibroblast migration and scar formation.

Fibroblasts proliferate after spinal cord in- further substantiating the importance of have been shown to cross the blood-brain
jury and contribute to scarring (11). Ruschel this neuronal subtype in functional re- barrier and inhibit axon regeneration (14).
et al. observed that epothilone B attenuated covery after spinal cord injury (12). How This systemic “cocktail” could further in-
fibrotic scar formation in vivo and propose serotonergic neurons respond to different clude a drug that enables neuronal growth
that the effect may be due to the drug’s ability treatments, including microtubule stabili- cones to bypass inhibitory components of
to decrease fibroblast migration. Fibroblasts zation, and how they robustly sprout after the extracellular matrix (15). In this way,
surrounding the edge of the dorsal hemisec- injury remain pressing questions. the differing molecular challenges of re-
tion lesion displayed a rounder shape and an The value of epothilone B treatment after covering from spinal cord injury may be
increase in stabilized tubulin when exposed spinal cord injury lies in its ability to mod- overcome, without the risk of exposing the
to the drug. Why is the drug’s effect on fibro- ulate both the inhibitory scar environment spinal cord, to allow for meaningful regen-
blasts seemingly opposite from its effect on and the regenerating potential of neurons eration and ultimately functional recovery
neurons? The authors propose the difference in a noninvasive manner (see the figure). from a devastating condition. ■
may be due to epothilone B’s interactions The dual effects point to the potential of
RE FE REN C ES
with tau, a microtubule-associating protein combinatorial strategies to target more
1. J. M. Cregg et al., Exp. Neurol. 253, 197 (2014).
enriched in neurons. than one underlying problem of a given 2. J. Ruschel et al., Science 348, 347 (2015).
Even more impressive is the ability of condition, such as spinal cord injury. More- 3. C. E. Hill, M. S. Beattie, J. C. Bresnahan, Exp. Neurol. 171,
epothilone B to drive axon outgrowth (in over, systemically delivered drugs represent 153 (2001).
4. R. y Cajal, Degeneration and Regeneration of the Nervous
vitro) across classically inhibitory sub- the next frontier of research in therapies for System, R. M. May, Transl. (Oxford Univ. Press, London,
strates such as Nogo-A, chondroitin sulfate injuries of the central nervous system. 1928).
proteoglycans, and semaphorin 3A (an ef- Aside from drugs that manage symptoms 5. V. J. Tom, M. P. Steinmetz, J. H. Miller, C. M. Doller, J. Silver,
J. Neurosci. 24, 6531 (2004).
fect that was abolished with nocodazole). caused by spinal cord injury, there are cur- 6. A. R. Filous et al., J. Neurosci. 34, 16369 (2014).
Injection of epothilone B into the rat body rently no drugs approved by the U.S. Food 7. A. Di Maio et al., J. Neurosci. 31, 4569 (2011).
cavity after dorsal column transection and Drug Administration to treat this trau- 8. A. Ertürk, F. Hellal, J. Enes, F. Bradke, J. Neurosci. 27, 9169
(2007).
transformed dystrophic growth cones into matic injury that allow for functional recov-
ILLUSTRATION: V. ALTOUNIAN/SCIENCE

9. H. Witte, D. Neukirchen, F. Bradke, J. Cell Biol. 180, 619


regenerating axons that could more readily ery. The systemic delivery of a drug such as (2008).
penetrate the scar compared to injured ani- epothilone B could therefore be a turning 10. F. Hellal et al., Science 331, 928 (2011).
11. C. Göritz et al., Science 333, 238 (2011).
mals injected with a control. After spinal point in treatment. Additionally, one could
12. R. van den Brand et al., Science 336, 1182 (2012).
contusion injury, epothilone B treatment combine this drug with intravenous deliv- 13. J. P. Bertram et al., Sci. Transl. Med. 1, 11ra22 (2009).
increased sprouting of neurons containing ery of synthetic platelets to stanch bleeding 14. S. A. Busch et al., J. Neurosci. 31, 944 (2011).
the neurotransmitter serotonin. Interest- (13), and with an immune-modulating ther- 15. B. T. Lang et al., Nature 518, 404 (2015).

ingly, the addition of a serotonin antagonist apy to allow for neuroprotection, as bone
abrogated gains in sensorimotor function, marrow–derived activated macrophages 10.1126/science.aab1615

286 17 APRIL 2015 • VOL 348 ISSUE 6232 sciencemag.org SCIENCE

Published by AAAS
LEE

Organelles
Overview

BEFORE
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IN SIG HTS | P E R S P E C T I V E S

Without epothilone B
Fibroblasts

Lesion in dorsal spinal cord Microtubules in


Scarring dystrophic growth cone

With epothilone B

Dual acting drug. After spinal cord injury, dystrophic growth cones fill with disorganized microtubules and axons cannot extend. Fibroblasts migrate to the lesion and contribute
to an environment that inhibits axon outgrowth. Systematically delivered epothilone B, which crosses the blood-brain barrier, stabilizes neuron microtubules and promotes axon
extension through the injured site. It also hampers fibroblast migration and scar formation.

Fibroblasts proliferate after spinal cord in- further substantiating the importance of have been shown to cross the blood-brain
jury and contribute to scarring (11). Ruschel this neuronal subtype in functional re- barrier and inhibit axon regeneration (14).
et al. observed that epothilone B attenuated covery after spinal cord injury (12). How This systemic “cocktail” could further in-
fibrotic scar formation in vivo and propose serotonergic neurons respond to different clude a drug that enables neuronal growth
that the effect may be due to the drug’s ability treatments, including microtubule stabili- cones to bypass inhibitory components of
to decrease fibroblast migration. Fibroblasts zation, and how they robustly sprout after the extracellular matrix (15). In this way,
surrounding the edge of the dorsal hemisec- injury remain pressing questions. the differing molecular challenges of re-
tion lesion displayed a rounder shape and an The value of epothilone B treatment after covering from spinal cord injury may be
increase in stabilized tubulin when exposed spinal cord injury lies in its ability to mod- overcome, without the risk of exposing the
to the drug. Why is the drug’s effect on fibro- ulate both the inhibitory scar environment spinal cord, to allow for meaningful regen-
blasts seemingly opposite from its effect on and the regenerating potential of neurons eration and ultimately functional recovery
neurons? The authors propose the difference in a noninvasive manner (see the figure). from a devastating condition. ■
may be due to epothilone B’s interactions The dual effects point to the potential of
RE FE REN C ES
with tau, a microtubule-associating protein combinatorial strategies to target more
1. J. M. Cregg et al., Exp. Neurol. 253, 197 (2014).
enriched in neurons. than one underlying problem of a given 2. J. Ruschel et al., Science 348, 347 (2015).
Even more impressive is the ability of condition, such as spinal cord injury. More- 3. C. E. Hill, M. S. Beattie, J. C. Bresnahan, Exp. Neurol. 171,
epothilone B to drive axon outgrowth (in over, systemically delivered drugs represent 153 (2001).
4. R. y Cajal, Degeneration and Regeneration of the Nervous
vitro) across classically inhibitory sub- the next frontier of research in therapies for System, R. M. May, Transl. (Oxford Univ. Press, London,
strates such as Nogo-A, chondroitin sulfate injuries of the central nervous system. 1928).
proteoglycans, and semaphorin 3A (an ef- Aside from drugs that manage symptoms 5. V. J. Tom, M. P. Steinmetz, J. H. Miller, C. M. Doller, J. Silver,
J. Neurosci. 24, 6531 (2004).
fect that was abolished with nocodazole). caused by spinal cord injury, there are cur- 6. A. R. Filous et al., J. Neurosci. 34, 16369 (2014).
Injection of epothilone B into the rat body rently no drugs approved by the U.S. Food 7. A. Di Maio et al., J. Neurosci. 31, 4569 (2011).
cavity after dorsal column transection and Drug Administration to treat this trau- 8. A. Ertürk, F. Hellal, J. Enes, F. Bradke, J. Neurosci. 27, 9169
(2007).
transformed dystrophic growth cones into matic injury that allow for functional recov-
ILLUSTRATION: V. ALTOUNIAN/SCIENCE

9. H. Witte, D. Neukirchen, F. Bradke, J. Cell Biol. 180, 619


regenerating axons that could more readily ery. The systemic delivery of a drug such as (2008).
penetrate the scar compared to injured ani- epothilone B could therefore be a turning 10. F. Hellal et al., Science 331, 928 (2011).
11. C. Göritz et al., Science 333, 238 (2011).
mals injected with a control. After spinal point in treatment. Additionally, one could
12. R. van den Brand et al., Science 336, 1182 (2012).
contusion injury, epothilone B treatment combine this drug with intravenous deliv- 13. J. P. Bertram et al., Sci. Transl. Med. 1, 11ra22 (2009).
increased sprouting of neurons containing ery of synthetic platelets to stanch bleeding 14. S. A. Busch et al., J. Neurosci. 31, 944 (2011).
the neurotransmitter serotonin. Interest- (13), and with an immune-modulating ther- 15. B. T. Lang et al., Nature 518, 404 (2015).

ingly, the addition of a serotonin antagonist apy to allow for neuroprotection, as bone
abrogated gains in sensorimotor function, marrow–derived activated macrophages 10.1126/science.aab1615

286 17 APRIL 2015 • VOL 348 ISSUE 6232 sciencemag.org SCIENCE

Published by AAAS
ec 3

Intracellular Support

Micro filament : cell Surface support & Mvt


Stability .

dynamic

diameter :
6- 8mm

50 50
monomer V. polymer → :

parallel polarity :
head →
tail
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monomer : G actin Polymer : Fact in ( dependent On Ca , ATD ,

& For min Protein driving polymer formation -


these control

the microfilaments structure I function :

myosin motor proteins ; kinases , Structural -


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viscosity of the cytoplasm -


gets :
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Actin : Anti -

viral Target ? HIV Therapy


Cy to chat as in inhibits act in blocking
-

polymerization by

new monomers to actin

competitive inhibitor by binding to end

Cy to Chala sin next anti -

HIV therapy ? NO -
it blocks all
.

polymerization of the cell

IF :