Wednesday, April 24, 2024
4/24/2024
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.
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