Development of a conditional ataxin-1 knockout mouse line

  • Didonna, Alessandro A (Investigador principal)

Detalles del proyecto

Descripción

Summary
Ataxin-1 is polyglutamine (polyQ) protein that operates as a chromatin-binding factor and gene repressor. In
recent years, ataxin-1 has been found implicated in multiple pathophysiological processes ranging from the
control of APP amyloidogenic cleavage to the modulation of neural precursor proliferation in the hippocampus.
Our group has also highlighted a novel immunomodulatory function for ataxin-1 targeting B cell responses in
central nervous system (CNS) autoimmunity. This experimental evidence adds an additional layer of complexity
to ataxin-1 research, which has been mainly focused on spinocerebellar ataxia type (SCA1)—a
neurodegenerative disorder caused by polyQ expansion mutations in ataxin-1. Importantly, all the efforts carried
out so far to characterize ataxin-1 function have relied only on global ataxin-1 null mice. However, the ubiquitous
expression of ataxin-1 and the complex cytoarchitecture of many tissues have complicated the systematic
analysis of all the molecular mechanisms controlled by ataxin-1 in different cell types and developmental stages.
To fill this gap, here we propose to develop a conditional ataxin-1 knockout mouse line using the binary Cre/Lox
system. This novel in vivo model will be instrumental to dissect the cell-autonomous and cell-mediated effects of
ataxin-1 in any target cytotype. In Specific Aim 1, we will employ CRISPR/Cas9 technology to introduce two
LoxP sites in the mouse genome, flanking one exon of the ataxin-1 encoding Atxn1 gene. In Specific Aim 2, we
will breed the newly generated floxed Atxn1 mouse line with a Cd19-Cre driver line to ablate ataxin-1 in the B
cell compartment. We will then induce the multiple sclerosis model experimental autoimmune encephalomyelitis
(EAE) in the conditional Atxn1 knockout mice, in order to study the contribution of ataxin-1 expression in B cells
to autoimmune demyelination. Altogether, the proposed aims hold the power to generate a new research tool
that will substantially advance the current understanding of ataxin-1 biology, with important implications and
lessons for several neurodegenerative diseases including multiple sclerosis and Alzheimer's disease.
EstadoFinalizado
Fecha de inicio/Fecha fin15/2/2331/1/24

Financiación

  • National Institute of Neurological Disorders and Stroke: USD75,500.00

!!!ASJC Scopus Subject Areas

  • Neurología clínica
  • Neurología

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