# Role of Ataxin-1 in BACE1 Expression and Alzheimer's Disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $413,030

## Abstract

Project Summary
 Recent efforts to uncover genetic factors responsible for Alzheimer's disease (AD) have identified
dozens of associated loci. Among these, our research group previously reported ATXN1 in a family-based AD
genome-wide association study. ATXN1 has been otherwise known for to harbor mutations causing
spinocerebellar ataxia type 1, a neurodegenerative disease that primarily impairs coordinated movement. In a
cell-based study, knockdown of Ataxin-1 gene (ATXN1) expression increased amyloidogenic processing of the
amyloid precursor protein (APP) and the secretion of A, the main component of senile plaques in AD brains.
In the preliminary examination of Ataxin-1 KO mice, we found Ataxin-1 regulates BACE1 expression,
selectively in AD-vulnerable brain regions. In AD mice, depletion of Ataxin-1 increased -secretase-cleavage of
APP, A deposition and gliosis in the cerebrum. Furthermore, Ataxin-1 KO impaired hippocampal
neurogenesis and axonal targeting, which are regulated by BACE1. To validate and expand upon these
findings, here, we propose to 1. Elucidate the molecular mechanism by which Ataxin-1 regulates BACE1
expression in the brain; 2. Assess the impact of Ataxin-1 loss of function on AD pathogenesis; and 3. Identify
and characterize novel AD-associated Ataxin-1 gene variants and/or mutations from AD DNA sample sets.
Specifically, for Aim 1, we will first determine whether Ataxin-1 regulates BACE1 mRNA level by affecting its
stability or by its transcription. To test this, we will employ acute brain slice cultures of Ataxin-1 KO and WT
mice, and examine the differential effects of transcriptional inhibitors on the steady-state level of BACE1 mRNA
and also measure newly synthesized BACE1 mRNA incorporating nucleotide analogs in the cultured slices.
We will then examine if Ataxin-1-interacting transcriptional factors bind to and regulate BACE1 promoter by
ChIP analysis. With regard to Aim 2, we will examine if the increased A plaque load and gliosis are
maintained in APP-PS1/ATXN1-KO mice at older age (9 month). To determine if impaired hippocampal
neurogenesis and axonal targeting are caused by increased BACE1, we will generate ATXN1 −/−:BACE1 +/−
mice and examine if the two deficits are rescued, as compared to ATXN1 −/− mice. Finally, in Aim 3, we will
identify ATXN1 mutations/variants that either increase risk or confer protection for AD by analysis of
WGS/WES data of NIMH, NIA and ADNI AD DNA sample sets. For the most associated mutations/variants, we
will examine their effects on BACE1 expression and APP processing by incorporating them into the genome of
human neuronal cells via CRISPR/Cas9 technology. At the completion of the proposed study, we believe we
will provide critically needed data addressing the role of Ataxin-1 in regulating BACE1 expression while also
facilitating novel therapies aimed at targeting BACE1 to prevent and treat AD.

## Key facts

- **NIH application ID:** 9912220
- **Project number:** 5R01AG056775-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Jaehong Suh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $413,030
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9912220

## Citation

> US National Institutes of Health, RePORTER application 9912220, Role of Ataxin-1 in BACE1 Expression and Alzheimer's Disease (5R01AG056775-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9912220. Licensed CC0.

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