A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction
- Lopez, A., Lee, S.E., Wojta, K., Ramos, E.M., Klein, E., Chen, J., Boxer, A.L., Gorno-Tempini, M.L., Geschwind, D.H., Schlotawa, L., Ogryzko, N.V., Bigio, E.H., Rogalski, E., Weintraub, S., Mesulam, M.M., Fleming, A., Coppola, G., Miller, B.L., Rubinsztein, D.C.
- Brain : a journal of neurology 140(4): 1128-1146 (Journal)
- Registered Authors
- Fleming, Angeleen, Ogryzko, Nikolay
- autophagy, neurodegeneration, proteasome, tauopathy
- MeSH Terms
- Autophagy-Related Protein 5
- Behavior, Animal
- Disease Models, Animal
- Embryo, Nonmammalian
- Frontotemporal Dementia/genetics
- Heredodegenerative Disorders, Nervous System/genetics*
- Heredodegenerative Disorders, Nervous System/therapy*
- Polymorphism, Single Nucleotide
- Proteasome Endopeptidase Complex/genetics
- Supranuclear Palsy, Progressive/genetics*
- Supranuclear Palsy, Progressive/therapy*
- Zebrafish Proteins
- tau Proteins/genetics*
- tau Proteins/metabolism
- 28334843 Full text @ Brain
Lopez, A., Lee, S.E., Wojta, K., Ramos, E.M., Klein, E., Chen, J., Boxer, A.L., Gorno-Tempini, M.L., Geschwind, D.H., Schlotawa, L., Ogryzko, N.V., Bigio, E.H., Rogalski, E., Weintraub, S., Mesulam, M.M., Fleming, A., Coppola, G., Miller, B.L., Rubinsztein, D.C. (2017) A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. Brain : a journal of neurology. 140(4):1128-1146.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and NotesThis article is corrected by ZDB-PUB-220906-65.