A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction

Tauopathy Genetics Consortium

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the gene encoding tau (MAPT) cause frontotemporal dementia spectrum disorders. A rare tau variant p.A152T was reported as a risk factor for frontotemporal dementia spectrum and Alzheimer's disease in an initial case-control study. Such findings need replication in an independent cohort. We analysed an independent multinational cohort comprising 3100 patients with neurodegenerative disease and 4351 healthy control subjects and found p.A152T associated with significantly higher risk for clinically defined frontotemporal dementia and progressive supranuclear palsy syndrome. To assess the functional and biochemical consequences of this variant, we generated transgenic zebrafish models expressing wild-type or A152T-tau, where A152T caused neurodegeneration and proteasome compromise. Impaired proteasome activity may also enhance accumulation of other proteins associated with this variant. We increased A152T clearance kinetics by both pharmacological and genetic upregulation of autophagy and ameliorated the disease pathology observed in A152T-tau fish. Thus, autophagy-upregulating therapies may be a strategy for the treatment for tauopathies.

Original languageEnglish
Pages (from-to)1128-1146
Number of pages19
JournalBrain
Volume140
Issue number4
Early online date9 Feb 2017
DOIs
Publication statusPublished - 1 Apr 2017

Keywords

  • autophagy
  • neurodegeneration
  • proteasome
  • tauopathy

Fingerprint

Dive into the research topics of 'A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction'. Together they form a unique fingerprint.

Cite this