Role of Ataxin-1 in BACE1 Expression and Axonal Targeting in the Cerebrum

Identification: Suh, Jaehong


Description

Role of Ataxin-1 in BACE1 Expression and Axonal Targeting in the Cerebrum
 
Jaehong Suh1*, Donna M. Romano1, Scott P. Herrick2, Basavaraj Hooli1, Mary K. Oram1, Kristina Mullin1, Wilma Wasco1, Jeremy D. Schmahmann3, Mark W. Albers2, Rudolph E. Tanzi1*
1Genetics and Aging Research Unit, MassGeneral Institute of Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School; 3Ataxia Unit, Cognitive Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
*Corresponding authors: Jaehong Suh (suh.jaehong@mgh.harvard.edu) and Rudolph E. Tanzi (tanzi@mgh.harvard.edu).
 
Expansion of CAG trinucleotide repeats in the Ataxin-1 gene (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordinated movement and cognitive functions. ATXN1 is associated with genetic risk for Alzheimer's disease (AD). Here, we show loss of Ataxin-1 potentiates AD pathogenesis. Specifically, knockout of Atxn1 in mice led to increased expression of β-secretase (BACE1) and elevated BACE1-mediated cleavage of the amyloid precursor protein (APP), selectively in AD-vulnerable brain regions. Ataxin-1 depletion exacerbated Aβ plaque deposition and gliosis in AD mice, and impaired hippocampal neurogenesis and axonal targeting. The SCA1-linked CAG repeat number was normal in AD patients. However, in SCA1 mice, aggregation of mutant Ataxin-1 led to BACE1 up-regulation and axonal targeting defects in the hippocampal CA2 region. Together, these findings indicate that loss of Ataxin-1 potentiates Aβ pathology, and BACE1 elevation may represent a shared pathogenic mechanism underlying cognitive deficits in SCA1 and AD.
 
 

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