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

Ana Lopez, Suzee E. Lee, Kevin Wojta, Eliana Marisa Ramos, Eric Klein, Jason Chen, Adam L. Boxer, Maria Luisa Gorno-Tempini, Daniel H. Geschwind, Lars Schlotawa, Nikolay V. Ogryzko, Eileen H. Bigio, Emily Rogalski, Sandra Weintraub, Marsel M. Mesulam, Angeleen Fleming, Giovanni Coppola, Bruce L. Miller, David C. Rubinsztein*, Federica AgostaAntonella Alberici, Gülsen Babacan-Yildiz, David A. Bennett, Kaya Bilguvar, Barbara Borroni, Ahmet O. Caglayan, Onofre Combarros, Giancarlo Comi, Etty P. Cortés, Isidre Ferrer, Şermin Genç, Murat Gunel, Karen H. Gylys, Begoña Indakoetxea, Clementine E. Karageorgiou, Anna Karydas, Ulkan Kilic, Adolfo Lopez De Munain, Giuseppe Magnani, Robert W. Mahley, Filippo Martinelli Boneschi, Jacqueline Martinez, Salvatore Mazzeo, Fermin Moreno, Alessandro Padovani, John Papatriantafyllou, Ekaterina Rogaeva, Pascual Sanchez-Juan, Roberto Santangelo, Gary W. Small, Tauopathy Genetics Consortium

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


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 (US)
Pages (from-to)1128-1146
Number of pages19
Issue number4
StatePublished - Apr 1 2017


  • autophagy
  • neurodegeneration
  • proteasome
  • tauopathy

ASJC Scopus subject areas

  • Clinical Neurology


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