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 journalArticle

30 Citations (Scopus)

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 (US)
Pages (from-to)1128-1146
Number of pages19
JournalBrain
Volume140
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

Frontotemporal Dementia
Autophagy
Zebrafish
Alleles
Proteasome Endopeptidase Complex
Tauopathies
Progressive Supranuclear Palsy
Neurodegenerative Diseases
Case-Control Studies
Healthy Volunteers
Alzheimer Disease
Fishes
Up-Regulation
Pharmacology
Pathology
Mutation
Therapeutics
Genes
Proteins

Keywords

  • autophagy
  • neurodegeneration
  • proteasome
  • tauopathy

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Lopez, A., Lee, S. E., Wojta, K., Ramos, E. M., Klein, E., Chen, J., ... Tauopathy Genetics Consortium (2017). A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. Brain, 140(4), 1128-1146. https://doi.org/10.1093/brain/awx005
Lopez, Ana ; Lee, Suzee E. ; Wojta, Kevin ; Ramos, Eliana Marisa ; Klein, Eric ; Chen, Jason ; Boxer, Adam L. ; Gorno-Tempini, Maria Luisa ; Geschwind, Daniel H. ; Schlotawa, Lars ; Ogryzko, Nikolay V. ; Bigio, Eileen H. ; Rogalski, Emily ; Weintraub, Sandra ; Mesulam, Marsel M. ; Fleming, Angeleen ; Coppola, Giovanni ; Miller, Bruce L. ; Rubinsztein, David C. ; Agosta, Federica ; Alberici, Antonella ; Babacan-Yildiz, Gülsen ; Bennett, David A. ; Bilguvar, Kaya ; Borroni, Barbara ; Caglayan, Ahmet O. ; Combarros, Onofre ; Comi, Giancarlo ; Cortés, Etty P. ; Ferrer, Isidre ; Genç, Şermin ; Gunel, Murat ; Gylys, Karen H. ; Indakoetxea, Begoña ; Karageorgiou, Clementine E. ; Karydas, Anna ; Kilic, Ulkan ; De Munain, Adolfo Lopez ; Magnani, Giuseppe ; Mahley, Robert W. ; Boneschi, Filippo Martinelli ; Martinez, Jacqueline ; Mazzeo, Salvatore ; Moreno, Fermin ; Padovani, Alessandro ; Papatriantafyllou, John ; Rogaeva, Ekaterina ; Sanchez-Juan, Pascual ; Santangelo, Roberto ; Small, Gary W. ; Tauopathy Genetics Consortium. / A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. In: Brain. 2017 ; Vol. 140, No. 4. pp. 1128-1146.
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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.",
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author = "Ana Lopez and Lee, {Suzee E.} and Kevin Wojta and Ramos, {Eliana Marisa} and Eric Klein and Jason Chen and Boxer, {Adam L.} and Gorno-Tempini, {Maria Luisa} and Geschwind, {Daniel H.} and Lars Schlotawa and Ogryzko, {Nikolay V.} and Bigio, {Eileen H.} and Emily Rogalski and Sandra Weintraub and Mesulam, {Marsel M.} and Angeleen Fleming and Giovanni Coppola and Miller, {Bruce L.} and Rubinsztein, {David C.} and Federica Agosta and Antonella Alberici and G{\"u}lsen Babacan-Yildiz and Bennett, {David A.} and Kaya Bilguvar and Barbara Borroni and Caglayan, {Ahmet O.} and Onofre Combarros and Giancarlo Comi and Cort{\'e}s, {Etty P.} and Isidre Ferrer and Şermin Gen{\cc} and Murat Gunel and Gylys, {Karen H.} and Bego{\~n}a Indakoetxea and Karageorgiou, {Clementine E.} and Anna Karydas and Ulkan Kilic and {De Munain}, {Adolfo Lopez} and Giuseppe Magnani and Mahley, {Robert W.} and Boneschi, {Filippo Martinelli} and Jacqueline Martinez and Salvatore Mazzeo and Fermin Moreno and Alessandro Padovani and John Papatriantafyllou and Ekaterina Rogaeva and Pascual Sanchez-Juan and Roberto Santangelo and Small, {Gary W.} and {Tauopathy Genetics Consortium}",
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Lopez, A, Lee, SE, Wojta, K, Ramos, EM, Klein, E, Chen, J, Boxer, AL, Gorno-Tempini, ML, Geschwind, DH, Schlotawa, L, Ogryzko, NV, Bigio, EH, Rogalski, E, Weintraub, S, Mesulam, MM, Fleming, A, Coppola, G, Miller, BL, Rubinsztein, DC, Agosta, F, Alberici, A, Babacan-Yildiz, G, Bennett, DA, Bilguvar, K, Borroni, B, Caglayan, AO, Combarros, O, Comi, G, Cortés, EP, Ferrer, I, Genç, Ş, Gunel, M, Gylys, KH, Indakoetxea, B, Karageorgiou, CE, Karydas, A, Kilic, U, De Munain, AL, Magnani, G, Mahley, RW, Boneschi, FM, Martinez, J, Mazzeo, S, Moreno, F, Padovani, A, Papatriantafyllou, J, Rogaeva, E, Sanchez-Juan, P, Santangelo, R, Small, GW & Tauopathy Genetics Consortium 2017, 'A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction', Brain, vol. 140, no. 4, pp. 1128-1146. https://doi.org/10.1093/brain/awx005

A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. / Lopez, Ana; Lee, Suzee E.; Wojta, Kevin; Ramos, Eliana Marisa; Klein, Eric; Chen, Jason; Boxer, Adam L.; Gorno-Tempini, Maria Luisa; Geschwind, Daniel H.; Schlotawa, Lars; Ogryzko, Nikolay V.; Bigio, Eileen H.; Rogalski, Emily; Weintraub, Sandra; Mesulam, Marsel M.; Fleming, Angeleen; Coppola, Giovanni; Miller, Bruce L.; Rubinsztein, David C.; Agosta, Federica; Alberici, Antonella; Babacan-Yildiz, Gülsen; Bennett, David A.; Bilguvar, Kaya; Borroni, Barbara; Caglayan, Ahmet O.; Combarros, Onofre; Comi, Giancarlo; Cortés, Etty P.; Ferrer, Isidre; Genç, Şermin; Gunel, Murat; Gylys, Karen H.; Indakoetxea, Begoña; Karageorgiou, Clementine E.; Karydas, Anna; Kilic, Ulkan; De Munain, Adolfo Lopez; Magnani, Giuseppe; Mahley, Robert W.; Boneschi, Filippo Martinelli; Martinez, Jacqueline; Mazzeo, Salvatore; Moreno, Fermin; Padovani, Alessandro; Papatriantafyllou, John; Rogaeva, Ekaterina; Sanchez-Juan, Pascual; Santangelo, Roberto; Small, Gary W.; Tauopathy Genetics Consortium.

In: Brain, Vol. 140, No. 4, 01.04.2017, p. 1128-1146.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction

AU - Lopez, Ana

AU - Lee, Suzee E.

AU - Wojta, Kevin

AU - Ramos, Eliana Marisa

AU - Klein, Eric

AU - Chen, Jason

AU - Boxer, Adam L.

AU - Gorno-Tempini, Maria Luisa

AU - Geschwind, Daniel H.

AU - Schlotawa, Lars

AU - Ogryzko, Nikolay V.

AU - Bigio, Eileen H.

AU - Rogalski, Emily

AU - Weintraub, Sandra

AU - Mesulam, Marsel M.

AU - Fleming, Angeleen

AU - Coppola, Giovanni

AU - Miller, Bruce L.

AU - Rubinsztein, David C.

AU - Agosta, Federica

AU - Alberici, Antonella

AU - Babacan-Yildiz, Gülsen

AU - Bennett, David A.

AU - Bilguvar, Kaya

AU - Borroni, Barbara

AU - Caglayan, Ahmet O.

AU - Combarros, Onofre

AU - Comi, Giancarlo

AU - Cortés, Etty P.

AU - Ferrer, Isidre

AU - Genç, Şermin

AU - Gunel, Murat

AU - Gylys, Karen H.

AU - Indakoetxea, Begoña

AU - Karageorgiou, Clementine E.

AU - Karydas, Anna

AU - Kilic, Ulkan

AU - De Munain, Adolfo Lopez

AU - Magnani, Giuseppe

AU - Mahley, Robert W.

AU - Boneschi, Filippo Martinelli

AU - Martinez, Jacqueline

AU - Mazzeo, Salvatore

AU - Moreno, Fermin

AU - Padovani, Alessandro

AU - Papatriantafyllou, John

AU - Rogaeva, Ekaterina

AU - Sanchez-Juan, Pascual

AU - Santangelo, Roberto

AU - Small, Gary W.

AU - Tauopathy Genetics Consortium

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

AB - 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.

KW - autophagy

KW - neurodegeneration

KW - proteasome

KW - tauopathy

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DO - 10.1093/brain/awx005

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