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The cytoskeleton in neurodegenerative diseases
Nigel J Cairns1, Virginia M-Y Lee, John Q Trojanowski
1Center 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. cairns@mail.med.upenn.edu
The Journal of Pathology
|October 21, 2004
Summary
Abnormal cytoskeletal protein aggregates, including intermediate filament (IF) proteins and tau, are hallmarks of neurodegenerative diseases. Genetic defects in IF and tau genes are directly linked to the cause and progression of these debilitating conditions.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Abnormal aggregates of cytoskeletal proteins, specifically neuronal intermediate filament (IF) proteins and microtubule-associated protein (MAP) tau, characterize numerous neurodegenerative diseases.
- Mutations in genes encoding IF proteins and tau are increasingly recognized as critical factors in disease pathogenesis.
Purpose of the Study:
- To review the direct link between IF and tau abnormalities and the etiology and pathogenesis of neurodegenerative diseases.
- To highlight the role of genetic defects and biochemical alterations in cytoskeletal proteins.
- To discuss the implications for developing therapeutic strategies.
Main Methods:
- Review of existing literature on genetic mutations and polymorphisms in IF and tau genes.
- Analysis of in vitro and transgenic animal models demonstrating the impact of mutations on protein function and aggregate formation.
- Discussion of neuropathological, biochemical, and molecular genetics approaches for disease classification.
Main Results:
- Mutations in IF genes are implicated in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis.
- Mutations and polymorphisms in tau genes are associated with frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration.
- Aberrant tau aggregates result from impaired protein function, altered fibrillization, or perturbed gene splicing.
Conclusions:
- Cytoskeletal protein abnormalities, particularly involving IF and tau, are central to the pathogenesis of neurodegenerative diseases.
- Identification of molecular and genetic defects facilitates experimental studies and the development of targeted therapies.
- Future research should focus on developing assays for molecules that inhibit abnormal IF and tau protein inclusions.