한빛사 논문
Jaehong Suh,1,9,* Donna M. Romano,1 Larissa Nitschke,2,3,4 Scott P. Herrick,5 Britt A. DiMarzio,1 Volodymyr Dzhala,5 Jun-Seok Bae,1 Mary K. Oram,1 Yuejiao Zheng,1 Basavaraj Hooli,1 Kristina Mullin,1 Vincenzo A. Gennarino,2,3,8 Wilma Wasco,1 Jeremy D. Schmahmann,6 Mark W. Albers,5 Huda Y. Zoghbi,2,3,4,7,* and Rudolph E. Tanzi1,*
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
2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
3 Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA
4 Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA
5 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, 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 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
8 Present address: Department of Genetics & Development, Pediatrics and Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA
9 Lead Contact
*Correspondence: Jaehong Suh, Huda Y. Zoghbi, Rudolph E. Tanzi
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.
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