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FTDP-17 tau mutations decrease the susceptibility of tau to calpain I digestion
1Department of Pharmacology, Birdsall Medical Research Building, Mayo Clinic Jacksonville, FL 32224, USA.
Abstract:
Frontal temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is caused by splice site and missense mutations in the tau gene, and characterized by the accumulation of filamentous tau in cerebral neurons and glia. The missense mutations reduce the ability of tau to promote microtubule assembly and increase the ability of tau to form filaments. In this report we demonstrate that mutants V337M and R406W are less susceptible than mutant P301L or corresponding wild type tau to degradation by calpain I. The differences were at least in part due to changes in accessibility of a cleavage site located about 100 amino acids off the carboxy-terminus. The results suggest that the pathogenesis of some forms of FTDP-17 may involve tau accumulation due to decreased proteolytic degradation.
Insights
Mutations in the tau gene cause Frontotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Certain tau mutations reduce degradation, leading to tau accumulation and disease pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative disease.
- It is characterized by the accumulation of filamentous tau in the brain.
- FTDP-17 is caused by mutations in the tau gene.
Purpose of the Study:
- To investigate the proteolytic degradation of specific tau mutations associated with FTDP-17.
- To determine if reduced degradation contributes to tau accumulation in FTDP-17.
Main Methods:
- Assessed the susceptibility of wild-type and mutant tau proteins (V337M, R406W, P301L) to degradation by calpain I.
- Analyzed the accessibility of a specific cleavage site on the tau protein.
Main Results:
- Mutants V337M and R406W showed reduced susceptibility to calpain I degradation compared to mutant P301L and wild-type tau.
- This difference was partly due to altered accessibility of a cleavage site near the carboxy-terminus.
Conclusions:
- Decreased proteolytic degradation of tau may play a role in the pathogenesis of some forms of FTDP-17.
- Specific tau mutations can impair degradation pathways, leading to protein accumulation.