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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Ataxin-1 / deficiency
  • Ataxin-1 / genetics
  • Ataxin-1 / metabolism*
  • Brain / metabolism*
  • Brain / pathology
  • CA2 Region, Hippocampal / metabolism
  • CA2 Region, Hippocampal / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Female
  • Gene Frequency
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Neurogenesis
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Trinucleotide Repeats / genetics
  • Up-Regulation


  • Amyloid beta-Protein Precursor
  • Ataxin-1
  • DNA-Binding Proteins
  • Etv4 protein, mouse
  • Etv5 protein, mouse
  • Proto-Oncogene Proteins c-ets
  • Transcription Factors
  • Amyloid Precursor Protein Secretases