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The cytoskeleton and disease

Article in The Journal of Pathology · November 2004

DOI: 10.1002/path.1665 · Source: PubMed

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Journal of Pathology
J Pathol 2004; 204: 351–354
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/path.1665

Introductory Article

The cytoskeleton and disease

Frans CS Ramaekers1 * and Fred T Bosman2
1 Department of Molecular Cell Biology, Research Institutes CARIM, GROW and EURON, University of Maastricht, PO Box 616, 6200 MD
Maastricht, The Netherlands
2 Department of Pathology, University of Lausanne, Rue du Bugnon 25, 1011 Lausanne, Switzerland

*Correspondence to: Abstract

Dr Frans CS Ramaekers,
Department of Molecular Cell
Biology (Box 17), University of
Maastricht, PO Box 616,
NL-6200 MD Maastricht,
The Netherlands.
E-mail:
f.ramaekers@molcelb.unimaas.nl
Cytoskeletal research in recent years has revolutionized cell biology and biomedicine. The
cytoskeleton spans the cytoplasm and interconnects the cell nucleus with the extracellular
matrix, thereby forming a structural link between molecules involved in cell communication
on the one hand, and gene expression on the other. Since the cytoskeleton is involved in
virtually all cellular processes, abnormalities in this essential cellular component frequently
result in disease. In this introduction, the basic structure of the cytoskeleton is briefly
outlined. Furthermore, the disease processes in which the cytoskeleton plays a decisive role,
and which are reviewed in detail in the papers in this issue, are briefly introduced. The
advances in our understanding of the cytoskeleton and its function in disease will lead to
new diagnostic and therapeutic applications in the foreseeable future.
Copyright  2004 Pathological Society of Great Britain and Ireland. Published by John
Wiley & Sons, Ltd.
Keywords: cytoskeleton; nuclear matrix; disease mechanisms

Introduction of the cytoskeletal apparatus, advancing cytoskeleton

Cytoskeletal research in recent years has revolution-
ized the field of cell biology and biomedicine, with the
accelerating emerging awareness of the complex inter-
play between cytoskeleton systems that provide the
framework for nearly all cellular processes. Cytoskele-
tal filaments occur throughout the entire animal and
plant kingdoms, and although micro-organisms may
not produce these structures themselves, they often
take advantage of them when infiltrating their eukary-
otic host.
Structure and function of the cytoskeleton
Cytoskeletal systems consist of several filamentous
networks that extend from the plasma membrane to
the nuclear envelope and even the interior of the
nucleus. The cytoskeleton also plays a role in anchor-
ing the cell to its neighbours and to the extracellu-
lar matrix via specialized cell junctions that span the
plasma membrane. A major fraction of total cellular
protein, over 80% in some cells, is of cytoskeletal
origin. The cytoskeleton is now known to consist of
hundreds of different (associated) proteins cooperat-
ing in the organization of the complex machinery that
is involved in essentially all structural and dynamic
aspects of living cells, including maintenance of cell
shape, cell movement, cell replication, apoptosis, cell
differentiation, and cell signalling [1]. In view of
the central importance and the incredible complexity
research has become one of the central challenges of
modern biology. Research in this field is now moving
very fast and will certainly contribute to the develop-
ment of more cytoskeleton targeted therapies in the
next 10 years. In particular, a greater understanding
of the cytoskeleton will provide benefits for diagnosis
and therapy of human diseases, in the development of
novel approaches for environmental monitoring, and
in novel biotechnology applications.
The cytoskeleton of eukaryotic cells is composed
of three major protein families that form filamentous
structures running throughout the cell, ie microfila-
ments consisting of different actin isoforms, micro-
tubules made of α- and β-tubulin, and the intermedi-
ate filaments, together with their associated molecular
motors and regulatory protein complexes. The micro-
filaments and microtubules are assembled from highly
conserved globular proteins, while the intermediate fil-
aments are built from extended proteins with a central
α-helical domain. Although these different proteins
have a conserved substructure, they are character-
ized by considerable divergence with respect to their
amino acid sequences in the non-α-helical head and
tail domains. Various members of the intermediate fil-
ament protein family are expressed in a tissue-specific
manner, as shown in Table 1. Next to these cytoplas-
mic filaments, the cell nucleus also contains supporting
structures, such as the nuclear lamina, containing the
lamins, one of the subfamilies of intermediate fila-
ment proteins. Finally, specific scaffolding structures
may exist directly underneath the plasma membrane

Copyright  2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
352 FCS Ramaekers et al

Table 1. Intermediate filament protein classification, composi- already used to inhibit cell division. The basic knowl-
tion, and tissue distribution edge of microtubule-assembly processes will in future
Protein Tissue lead to more specific drugs that have fewer effects
Subtype composition distribution on healthy cells. Antibodies to the cytoskeleton are
widely used for diagnostic purposes; for example, in
Type I Acidic keratins Epithelia
cancer typing [3]. Research into the function, control,
Type II Basic keratins Epithelia and maintenance of the cytoskeleton is therefore of
Type III Vimentin Mesenchymal cells major interest, not only to molecular biologists, cell
Desmin Muscle cells biologists, and biochemists, but also to the medical,
Glial fibrillary acidic Glial cells, astrocytes, veterinary, and agricultural community.
protein (GFAP) stellate liver cells
The purpose of this review issue is to provide an
Peripherin Diverse neuronal cells
Synemin Muscle cells update of cytoskeletal research, as it impacts on pathol-
ogy. A wide range of topics has been chosen, to exem-
Type IV NF-L Neurons
NF-M Neurons
plify the significance of cytoskeleton knowledge for
NF-H Neurons understanding disease mechanisms. We chose not to
Nestin Neuroepithelial stem highlight the use of anti-cytoskeletal protein antibodies
cells, muscle cells in pathology, as this is a field in itself, well developed
α-Internexin Neurons and broadly accepted, and less important in terms of
Syncoilin Muscle cells
disease mechanisms [3]. A variety of cytoskeletal pro-
Type V Nuclear lamins All cell types teins were selected for discussion, as well as a range
Unclassified Phakinin Lens of organ systems, in which abnormalities of these pro-
Filensin Lens teins are responsible for often intriguing pathological
processes. Any attempt to be comprehensive would
have been futile, given the scope of the field and the
of specific cell types, such as the erythroid membrane explosion of knowledge.
cytoskeleton. The first three papers deal with the role that cytok-
The functions attributed to these scaffolding fibres eratins play in congenital and acquired diseases in
are manifold, but can be summarized as (a) functions different organs. Lane and McLean [4] discuss keratins
that govern cell motility, (b) functions that gov- and skin diseases. The association of keratin mutations
ern cell proliferation, (c) functions that control and with genetic skin fragility disorders constitutes one of
maintain cell morphology and tissue stability, and the most striking examples of cytoskeleton disorders.
(d) functions in cell communication and intracellu- This has served as a paradigm for many other diseases
lar signal transduction [2]. The extensive cross-talk and has been highly informative for the study of inter-
between cytoskeleton systems is becoming recognized mediate filaments and their associated components,
as critical for cell–matrix interactions and for main- elucidating the importance of this group of proteins
tenance of nuclear structure and function. In the past for cell structure. These diseases have convincingly
few years, the role of the cytoskeleton in multiple sig- shown that, at least in the case of epidermal keratins,
nal transduction pathways has been elucidated at the providing physical resilience to epithelial cells is their
molecular level. key function. Zatloukal and Denk [5] review how the
keratin cytoskeleton is affected in liver diseases. Ker-
atin intermediate filaments have been identified as a
The cytoskeleton and disease major intracellular target in a variety of liver diseases
such as alcoholic and non-alcoholic steatohepatitis,
Cytoskeletal protein aberrations are the underlying copper toxicosis, and cholestasis. Keratin gene knock-
reason for many pathological phenotypes. It is no out mice have provided insight into the role of ker-
surprise that modifications in such a crucial cellu- atins in the hepatocyte: they are not merely providing
lar structure lead to pathological conditions. Indeed, mechanical stability as a key element in cellular struc-
many diseases have now been associated with abnor- ture, but constitute a target of toxic stress, the effects
malities in cytoskeletal and nucleoskeletal proteins, of which on the hepatocyte they modulate. The triad
including several cardiovascular disease syndromes, is completed by Owens and Lane [6], with a paper
neurodegeneration, cancer (invasion), liver cirrho- on keratin mutations and intestinal pathology. Lim-
sis, pulmonary fibrosis, and blistering skin diseases. ited evidence exists for simple keratin involvement
The mechanisms by which many micro-organisms in disease. Mutations in simple keratins have been
infect specific cells have been shown to depend on found in patients with liver cirrhosis and chronic pan-
host cytoskeletal elements. Attempts to modulate the creatitis, and recently mutations in the simple keratin
cytoskeleton by peptides or other specific drugs have K8 were found in patients with inflammatory bowel
already yielded interesting results and this will lead disease. The effects of mutations in simple keratins
to new therapeutic agents in the foreseeable future. would be expected to have mild effects on cells and
The impact on cancer treatment is a convincing exam- indeed, distinct but less severe cellular abnormalities
ple: anti-cytoskeletal (microtubule targeted) drugs are have been found. The authors discuss the evidence

J Pathol 2004; 204: 351–354

The cytoskeleton and disease
that these mutations constitute a predisposing factor
for inflammatory bowel disease.
The next section deals with actins in inflamma-
tion and repair. Chaponnier and Gabbiani [7] discuss
actin isoforms in human disease. α-Smooth muscle
actin has allowed us to identify the role of vascu-
lar smooth muscle cells in vascular development and
vascular diseases and the role of myofibroblasts in
wound healing, fibrocontractive diseases, and stromal
reaction in cancer. The hallmark of a differentiated
myofibroblast is an organized contractile apparatus
consisting of α-smooth muscle actin-containing stress
fibres. Recent data suggest that α-smooth muscle actin
plays a direct role in myofibroblast contractile activity
through its N-terminal domain AcEEED. Newly devel-
oped antibodies against α-skeletal and α-cardiac actins
have shown that subpopulations of α-skeletal posi-
tive cardiomyocytes exist in the failing heart. Actin
isoforms might be important in human disease but
this needs to be further investigated. In the paper
by Rottner et al [8], evidence is reviewed showing
that in invading the host, infectious micro-organisms
exploit the actin cytoskeleton. They have to overcome
host defence mechanisms, which include mechanical
and chemical barriers at the surface of the skin and
mucous membranes, innate immunity, and the spe-
cific immune response. Only by clearing these barriers
might micro-organisms reach the niche from which
they can develop their pathogenic effects. Some micro-
organisms have been found to induce actin rearrange-
ments at the surface of infected host cells, resulting
in the formation of pseudopod-like structures beneath
intimately attached bacteria.
In the following section, a series of papers highlight
the role that cytoskeletal abnormalities play in muscle-
and neurodegenerative diseases. Clarkson et al [9]
review the crucial role of actin cytoskeletal abnormali-
ties in the development of congenital myopathy. Con-
genital myopathies constitute a heterogeneous group
of disorders characterized by skeletal muscle weak-
ness. Three major forms have been identified: actin
myopathy, intra-nuclear rod myopathy, and nemaline
myopathy. So far, five genes have been linked to
congenital myopathy including α-actin, α- and β-
tropomyosin, troponin-T, and nebulin; all are com-
ponents of the thin filament of the sarcomere. The
mutations identified within these genes have varying
impacts on protein structure and give rise to different
forms of congenital myopathies. Greater understand-
ing of muscle formation and cause of disease has
been and will continue to be gained from the study
of the effect of mutations on protein function. Paulin
et al [10] then discuss desminopathies in muscle dis-
ease. Desmin abnormalities lead to disorganization and
loss of the desmin filament network and the accu-
mulation of insoluble aggregates in striated muscles
which destroy cell structure and interfere with func-
tion. Genes encoding desmin-associated proteins such
as alpha-B-crystallin may also be involved. Knock-out
mice have helped to reveal the fundamental role of
353
desmin filaments in cell architecture, sarcomere align-
ment, myofibril organization, and the distribution of
mitochondria. How intermediate filaments function in
astroglial cells especially under severe mechanical or
osmotic stress, in hypoxia, and in brain and spinal cord
injury is reviewed by Pekny and Pekna [11]. Astocytes
are the most abundant cells in the mammalian cen-
tral nervous system (CNS), yet knowledge about their
function in health and disease is limited. Recent exper-
imental data in mice show that when astrocyte interme-
diate filaments are ablated, reactive gliosis in various
CNS diseases is altered and the signs of CNS degen-
eration become more prominent. Dominant mutations
in the GFAP gene have been shown to lead to Alexan-
der disease, a fatal neurodegenerative condition in
humans. This is further elaborated in the paper by
Cairns et al [12], which focuses on the cytoskeleton
in neurodegenerative diseases. The discovery of muta-
tions in neuronal intermediate filament and tau genes
had firmly established the importance of neuronal
intermediate filament proteins and tau in the patho-
genesis of neurodegenerative disease. Intermediate fil-
ament gene mutations cause Charcot–Marie–Tooth
disease and amyotropic lateral sclerosis. Tau gene
mutations are responsible for fronto-temporal demen-
tia with parkinsonism and tau polymorphisms are risk
factors for progressive supranuclear palsy and corti-
cobasilar degeneration. In vitro studies and transgenic
animal models are presently being exploited to eluci-
date genotype–phenotype correlations and the details
of cytoskeletal protein functions in cells of the nervous
system.
The next group of papers deals with the role
of cytoskeletal proteins in diseases of the lympho-
haematological system. Birkenmeier and Barker [13]
review how mutations in the genes encoding ery-
throid membrane skeletal proteins lead to hereditary
haemolytic anaemias. Although the anaemia is usu-
ally the primary concern for the patient suffering from
spherocytosis or elliptocytosis, primary or secondary
effects are also encountered in other organ systems,
as the seven erythroid membrane proteins are also
expressed in a variety of other tissues. An exam-
ple is the protein 4.1R, of which a deficiency leads
to neurological symptoms. Research in this area is
essential because the more known about the genetic
mechanisms and the functional corollary of a gene
mutation, the better will the developers of gene ther-
apy (or other therapeutic modalities) be able to tar-
get the therapeutic approach. Calle et al [14] review
the adhesive and motile behaviour of dendritic cells
and the role of their cytoskeleton in cell adhesion
and migration. As migration and cell–cell adhesion
constitute essential elements in the development of
an acquired immune response, disturbances of den-
dritic cell motility and adhesion have serious effects
on the function of the immune system. This is the
case in patients with the Wiskott–Aldrich syndrome
(WAS), a syndrome characterized by immune dysreg-
J Pathol 2004; 204: 351–354
354
Figure 1. Visualisation of the microtubule cytoskeleton (red)
and its close association with the nuclear lamina (green).
Illustration provided by Dr JLV Broers, University of Maastricht,
The Netherlands
ulation and microthrombocytopenia, and which lack
the Wiskott–Aldrich syndrome protein (WASP). The
mechanisms responsible for the pathophysiology of
WAS are directly linked to deficient actin organization
in haematopoietic cells. Exactly how a WASP defect
leads to WAS remains, however, to be elucidated.
The next paper deals with the particularities of
the cytoskeleton in ciliated cells. Afzelius [15] dis-
cusses how anomalies in the cytoskeleton of cilia cause
the immotile cilia syndrome. Furthermore, the mecha-
nisms responsible for the additional manifestations of
functional defects of cilia are reviewed.
Because of its intimate interaction with the cytos-
keleton, Broers et al [16] review the role that the
nuclear lamina plays in the cell nucleus and in cell
structure (Figure 1). Nuclear lamins form a fibrous
nucleoskeletal network of intermediate-sized filaments
that underlies the inner nuclear membrane, and have
profound influences on nuclear structure and func-
tion, as they are building blocks on the one hand,
and transcription regulators on the other. Which of
these identities underlies the laminopathies, a spectrum
of genetic diseases caused by mutations in lamins or
lamin-associated proteins, is still a matter of specula-
tion, but recent studies have shed more light on the
cell biological basis of these pathologies.
J Pathol 2004; 204: 351–354
FCS Ramaekers et al
The last paper of this review issue is dedicated to
septins. Hall and Russell [17] argue convincingly why
these proteins, which were discovered in yeast and
have diverse cellular roles including polarity determi-
nation, cytoskeletal organization, membrane dynam-
ics, vesicle trafficking, and exocytosis, belong in a
cytoskeleton context. They do interact significantly
with the cytoskeleton, notably actin and tubulin. There
is substantial evidence to support the notion that
septins play a role in neoplasia, neurodegenerative dis-
eases, and infections.
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