The cytoskeleton in neurodegenerative diseases (CMT mentioned)

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Abstract from J Pathol. 2004 Oct 19;204(4):438-449

The cytoskeleton in neurodegenerative diseases. (CMT mentioned)

Cairns NJ, Lee VM, Trojanowski JQ.

Center for Neurodegenerative Disease Research, Department of Pathology

and Laboratory Medicine, and Institute on Aging, University of

Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA.

Abundant abnormal aggregates of cytoskeletal proteins are

neuropathological signatures of many neurodegenerative diseases that are

broadly classified by filamentous aggregates of neuronal intermediate

filament (IF) proteins, or by inclusions containing the

microtubule-associated protein (MAP) tau. The discovery of mutations in

neuronal IF and tau genes firmly establishes the importance of neuronal

IF proteins and tau in the pathogenesis of neurodegenerative diseases.

Multiple IF gene mutations are pathogenic for Charcot-Marie-Tooth (CMT)

disease and amyotrophic lateral sclerosis (ALS)-in addition to those in

the copper/zinc superoxide dismutase-1 (SOD1) gene. Tau gene mutations

are pathogenic for frontotemporal dementia with parkinsonism linked to

chromosome 17 (FTDP-17), and tau polymorphisms are genetic risk factors

for sporadic progressive supranuclear palsy (PSP) and corticobasal

degeneration (CBD). Thus, IF and tau abnormalities are linked directly

to the aetiology and pathogenesis of neurodegenerative diseases. In

vitro and transgenic animal models are being used to demonstrate that

different mutations impair protein function, promote tau fibrilization,

or perturb tau gene splicing, leading to aberrant and distinct tau

aggregates. For recognition of these disorders at neuropathological

examination, immunohistochemistry is needed, and this may be combined

with biochemistry and molecular genetics to properly determine the

nosology of a particular case. As reviewed here, the identification of

molecular genetic defects and biochemical alterations in cytoskeletal

proteins of human neurodegenerative diseases has facilitated

experimental studies and will promote the development of assays of

molecules which inhibit abnormal neuronal IF and tau protein inclusions.

Copyright © 2004 Pathological Society of Great Britain and Ireland.

Published by Wiley & Sons, Ltd.