Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

INTERMEDIATE FILAMENTS AND SEPTINS
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skin their special toughness. Individuals with mutations in the gene encoding filaggrin
are strongly predisposed to dry skin diseases such as eczema.
Mutations in keratin genes cause several human genetic diseases. For example,
when defective keratins are expressed in the basal cell layer of the epidermis,
they produce a disorder called epidermolysis bullosa simplex, in which the skin
blisters in response to even very slight mechanical stress, which ruptures the basal
cells (Figure 16–69). Other types of blistering diseases, including disorders of the
mouth, esophageal lining, and the cornea of the eye, are caused by mutations in
the different keratins whose expression is specific to those tissues. All of these
maladies are typified by cell rupture as a consequence of mechanical trauma
and a disorganization or clumping of the keratin filament cytoskeleton. Many of
the specific mutations that cause these diseases alter the ends of the central rod
domain, demonstrating the importance of this particular part of the protein for
correct filament assembly.
Members of another family of intermediate filaments, called neurofilaments,
are found in high concentrations along the axons of vertebrate neurons (Figure
16–70). Three types of neurofilament proteins (NF-L, NF-M, and NF-H) coassemble
in vivo, forming heteropolymers. The NF-H and NF-M proteins have lengthy
C-terminal tail domains that bind to neighboring filaments, generating aligned
arrays with a uniform interfilament spacing. During axonal growth, new neurofilament
subunits are incorporated all along the axon in a dynamic process that
involves the addition of subunits along the filament length as well as the ends.
After an axon has grown and connected with its target cell, the diameter of the
axon may increase as much as fivefold. The level of neurofilament gene expression
seems to directly control axonal diameter, which in turn influences how
fast electrical signals travel down the axon. In addition, neurofilaments provide
strength and stability to the long cell processes of neurons.
The neurodegenerative disease amyotrophic lateral sclerosis (ALS, or Lou
Gehrig’s disease) is associated with an accumulation and abnormal assembly
of neurofilaments in motor neuron cell bodies and in the axon, aberrations that
may interfere with normal axonal transport. The degeneration of the axons leads
to muscle weakness and atrophy, which is usually fatal. The overexpression of
human NF-L or NF-H in mice results in mice that have an ALS-like disease. However,
a causative link between neurofilament pathology and ALS has not been
firmly established.
basal cell of epidermis
(A)
40 µm
(B)
basal lamina
hemidesmosomes
(C)
defective keratin
filament network
Figure 16–69 Blistering of the skin caused by a mutant keratin gene. A mutant gene encoding a truncated keratin protein (lacking both the
N- and C-terminal domains) was expressed in a transgenic mouse. The defective protein assembles with the normal keratins and thereby disrupts
the keratin filament network in the basal cells of the skin. Light micrographs of cross sections of (A) normal and (B) mutant skin show that the
blistering results from the rupturing of cells in the basal layer of the mutant epidermis (short red arrows). (C) A sketch of three cells in the basal
layer of the mutant epidermis, as observed by electron microscopy. As indicated by the red arrow, the cells rupture between the nucleus and the
hemidesmosomes (discussed in Chapter 19), which connect the keratin filaments to the underlying basal lamina. (From P.A. Coulombe et al., J. Cell
Biol. 115:1661–1674, 1991. With permission from The Rockefeller MBoC6 m16.21/16.71
University Press.)