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Cell. 2019 Aug 22;178(5):1159-1175.e17. doi: 10.1016/j.cell.2019.07.043.

Loss of Ataxin-1 Potentiates Alzheimer's Pathogenesis by Elevating Cerebral BACE1 Transcription.

Author information

1
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.
2
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.
3
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, TX 77030, USA.
4
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
5
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.
6
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.
7
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, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hzoghbi@bcm.edu.
8
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.

Abstract

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 Aβ 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 Aβ pathology, rendering it a potential contributor to AD risk and pathogenesis.

KEYWORDS:

Alzheimer’s disease; Aβ; BACE1; CA2; amyloid precursor protein; ataxin-1; axonal targeting; hippocampal neurogenesis; neurodegeneration; spinocerebellar ataxia type 1

PMID:
31442405
PMCID:
PMC6726125
[Available on 2020-08-22]
DOI:
10.1016/j.cell.2019.07.043

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