A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction.
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.
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Ana
A
Lopez
Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
Suzee E
SE
Lee
Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Kevin
K
Wojta
Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Eliana Marisa
EM
Ramos
Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Eric
E
Klein
Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Jason
J
Chen
Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
Adam L
AL
Boxer
Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
Maria Luisa
ML
Gorno-Tempini
Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Daniel H
DH
Geschwind
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Lars
L
Schlotawa
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
Nikolay V
NV
Ogryzko
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, IL 60611, USA.
Eileen H
EH
Bigio
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, IL 60611, USA.
Emily
E
Rogalski
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, IL 60611, USA.
Sandra
S
Weintraub
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, IL 60611, USA.
Marsel M
MM
Mesulam
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.|Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Angeleen
A
Fleming
Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Giovanni
G
Coppola
Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
Bruce L
BL
Miller
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK.
David C
DC
Rubinsztein
D000483:Alleles; D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian; D057180:Frontotemporal Dementia / Q000235:genetics; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D007700:Kinetics; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D013494:Supranuclear Palsy, Progressive / Q000235:genetics* / Q000628:therapy*; D024801:Tauopathies / Q000235:genetics* / Q000523:psychology / Q000628:therapy*; D015027:Zebrafish; D029961:Zebrafish Proteins; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
C572697:Atg5 protein, zebrafish; D000071187:Autophagy-Related Protein 5; D029961:Zebrafish Proteins; D016875:tau Proteins; D012313:RNA; D046988:Proteasome Endopeptidase Complex
autophagy; neurodegeneration; proteasome; tauopathy