Interrogating the necessity of neuronal contributions to SCA3

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

ABSTRACT Spinocerebellar ataxia type 3 (SCA3) is a debilitating neurodegenerative disorder characterized by impaired balance and coordination, and it currently has no effective treatment. SCA3 is the most prevalent dominantly inherited ataxia and is caused by a CAG repeat expansion in the ATXN3 gene. Although ATXN3 is expressed throughout the body, its’ aggregates cause dysfunction in specific cell types, including neurons and glia, in vulnerable central nervous system regions. Previous research suggests that neurons play a crucial role in driving SCA3, as overexpression of mutant ATXN3 specifically in neurons is sufficient to cause ataxic symptoms in a mouse model. However, it is still unknown whether neuronal mutant ATXN3 expression is necessary for SCA3, which could be key for therapeutic development. To investigate this, our lab created a novel conditional “off” knock-in Atxn3cQ300/Q6 mouse model that allows for the selective silencing of mutant ATXN3 in specific cell types. Validation of this model in the absence of Cre expression, shows they exhibit the well-established SCA3 pathophysiological features of disease such as progressive motor impairment, nuclear ATXN3 accumulation, and significant pathological and transcriptional dysregulation in neurons, oligodendrocytes, astrocytes, and microglia. By breeding this model with mice expressing neuron-specific Cre, we will determine whether neuronal expression of mutant ATXN3 is necessary for the motor deficits and pathological signatures in neurons and glia. These studies are expected to provide critical insights into the cellular mechanisms of SCA3, which could have a direct impact on therapeutic development. Additionally, this project will provide me with extensive experience and training in experimental design, bioinformatic data analysis, and scientific communication, which will prepare me for a career as an independent scientific investigator focusing on neuron-glia interactions in neurodegeneration.