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Missense tau mutations identified in FTDP-17 have a small effect on tau-microtubule interactions
1Departments of Pharmacology, Biochemistry and Molecular Biology, Birdsall Medical Research Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Abstract:
Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is a group of related disorders frequently characterized by the formation of tau inclusions in neurons and glial cells. To determine whether the formation of tau inclusions in FTDP-17 results from an alteration in the ability of mutant tau to maintain the microtubule (MT) system, we compared wild type four-repeat tau with three FTDP-17 mutants (P301L, V337M and R406W) for their ability to bind MT, promote MT assembly and bundling. According to in vitro binding and assembly assays, P301L is the only mutant that demonstrates a small, yet significant reduction, in its affinity for MT while both P301L and R406W have a small reduction in their ability to promote tubulin assembly. Based on studies of neuroblastoma and CHO cells transfected with GFP-tagged tau DNA constructs, both mutant and wild type tau transfectants were indistinguishable in the distribution pattern of tau in terms of co-localization with MT and generation of MT bundles. These results suggest that missense mutation of tau gene do not have an immediate impact on the integrity of MT system, and that exposure of affected neurons to additional insults or factors (e.g., aging) may be needed to initiate the formation of tau inclusions in FTDP-17.
Insights
Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutations do not immediately disrupt microtubule integrity. Additional factors may be required for tau inclusions to form in affected neurons.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is characterized by tau inclusions in neurons and glial cells.
- The precise mechanism leading to tau inclusion formation in FTDP-17 remains unclear.
Purpose of the Study:
- To investigate whether mutations in the tau gene alter its ability to maintain the microtubule (MT) system in FTDP-17.
- To compare the MT binding, assembly, and bundling capabilities of wild-type tau with three FTDP-17 mutants (P301L, V337M, R406W).
Main Methods:
- In vitro binding and assembly assays were performed using wild-type and mutant tau proteins.
- Studies involved transfecting neuroblastoma and CHO cells with GFP-tagged tau DNA constructs to assess tau distribution and MT interactions.
Main Results:
- The P301L mutant showed a small but significant reduction in MT binding affinity.
- Both P301L and R406W mutants exhibited a slight decrease in their ability to promote tubulin assembly.
- Transfected cells with both wild-type and mutant tau were indistinguishable in tau distribution, MT co-localization, and MT bundling.
Conclusions:
- Missense mutations in the tau gene do not appear to have an immediate impact on microtubule system integrity.
- The formation of tau inclusions in FTDP-17 may necessitate additional cellular insults or factors, such as aging, to be initiated.