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Loss of Ataxin-1 Potentiates Alzheimer's Pathogenesis by Elevating Cerebral BACE1 Transcription.
Suh, Jaehong; Romano, Donna M; Nitschke, Larissa; Herrick, Scott P; DiMarzio, Britt A; Dzhala, Volodymyr; Bae, Jun-Seok; Oram, Mary K; Zheng, Yuejiao; Hooli, Basavaraj; Mullin, Kristina; Gennarino, Vincenzo A; Wasco, Wilma; Schmahmann, Jeremy D; Albers, Mark W; Zoghbi, Huda Y; Tanzi, Rudolph E.
Afiliación
  • Suh J; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. Electronic address: suh.jaehong@mgh.harvard.edu.
  • Romano DM; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Nitschke L; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston
  • Herrick SP; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • DiMarzio BA; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Dzhala V; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Bae JS; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Oram MK; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Zheng Y; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Hooli B; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Mullin K; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Gennarino VA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
  • Wasco W; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Schmahmann JD; Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • Albers MW; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
  • Zoghbi HY; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston
  • Tanzi RE; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. Electronic address: tanzi@helix.mgh.harvard.edu.
Cell ; 178(5): 1159-1175.e17, 2019 08 22.
Article en En | MEDLINE | ID: mdl-31442405
Expansion of CAG trinucleotide repeats in ATXN1 causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordination and cognition. While ATXN1 is associated with increased Alzheimer's disease (AD) risk, CAG repeat number in AD patients is not changed. Here, we investigated the consequences of ataxin-1 loss of function and discovered that knockout of Atxn1 reduced CIC-ETV4/5-mediated inhibition of Bace1 transcription, leading to increased BACE1 levels and enhanced amyloidogenic cleavage of APP, selectively in AD-vulnerable brain regions. Elevated BACE1 expression exacerbated Aß deposition and gliosis in AD mouse models and impaired hippocampal neurogenesis and olfactory axonal targeting. In SCA1 mice, polyglutamine-expanded mutant ataxin-1 led to the increase of BACE1 post-transcriptionally, both in cerebrum and cerebellum, and caused axonal-targeting deficit and neurodegeneration in the hippocampal CA2 region. These findings suggest that loss of ataxin-1 elevates BACE1 expression and Aß pathology, rendering it a potential contributor to AD risk and pathogenesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer / Ataxina-1 Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Cell Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer / Ataxina-1 Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Cell Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos