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FTDP-17 Tau Mutations Induce Distinct Effects on Aggregation and Microtubule Interactions

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Combs, Benjamin, Gamblin, T. Chris·2012·Biochemistry
DOI 10.1021/bi3010818PMC PMC3548947
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Abstract

FTDP-17 mutations in the tau gene lead to early onset frontotemporal dementias characterized by the pathological aggregation of the microtubule-associated protein tau. Tau aggregation is closely correlated with the progression and severity of localized atrophy of certain regions in the brain. These mutations are primarily located in or near the microtubule-binding repeat regions of tau and can have vastly different effects on the protein. Some mutations have been linked to effects such as increased levels of aggregation, hyperphosphorylation, defects in mRNA splicing, and weakened interaction with microtubules. Given the differential effects of the mutations, it may not be surprising that the pathology associated with FTDP-17 can vary widely as well. Despite this variety, several of the mutations are commonly used interchangeably as aggregation inducers for in vitro and in vivo models of tauopathies. We generated recombinant forms of 12 FTDP-17 mutations chosen for their predicted effects on the charge, hydrophobicity, and secondary structure of the protein. We then examined the effects that the mutations had on the properties of in vitro aggregation of the protein and its ability to stabilize microtubule assembly. The group of mutations induced very different effects on the total amount of aggregation, the kinetics of aggregation, and filament morphology. Several of the mutations inhibited the microtubule stabilization ability of tau, while others had very little effect compared to wild-type tau. These results indicate that the mechanisms of disease progression may differ among FTDP-17 mutations and that the effects of the varying mutations may not be equal in all model systems.

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  • Structural properties of these tau variants will result in faster nucleation and elongation rates or stabilization of a particular molecular fold that can favour amyloidogenicity to produce unique pathologic properties when combined with Aβ pathology.

    “This was based on the premise that structural properties of these tau variants will result in faster nucleation and elongation rates (39), or the stabilization of particular molecular fold that can favour amyloidogenicity to produce unique pathologic properties when combined with Aβ pathology.”

    From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [39]

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Cited by

Sorted by citations

Authors
Combs, B., & Gamblin, T. C.
Affiliations
University of Kansas (US)
Corresponding author
Gamblin, T. Chris
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2012-10-18
Volume
51
Issue
43
Pages
8597-8607
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi3010818
PMC
PMC3548947
OpenAlex
W2084085802
Cited by
79
References
1
Citations by year
2026: 5 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 3 · 2020: 8 · 2019: 8 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 8 · 2014: 6 · 2013: 5
FWCI
4.07
Type
journal article
Language
en
Open access
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • KU ScholarWorks (The University of Kansas) (submittedVersion)
Funders
  • National Institute on Aging (K02AG025898)
  • National Institute of General Medical Sciences (GM103418., P20GM103418)
  • National Institute of Neurological Disorders and Stroke (R01NS083391)
  • National Center for Research Resources (P41RR002250)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
FTDP-17, tau protein, tau mutations, tau aggregation, microtubule stabilization, tauopathy, frontotemporal dementia, microtubule-binding repeats, aggregation kinetics, filament morphology, disease progression mechanisms
MeSH terms
Humans, Microtubules, Mutation, Tubulin, tau Proteins, Tauopathies

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