Identifying Cell-Type-Specific Mechanisms Contributing Toward the Progression of Polyglutamine Diseases

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Interdepartmental Neuroscience Program

First Advisor

Lim, Janghoo

Abstract

Neurodegenerative diseases pose an increasing societal burden, characterized by progressive symptoms that result in widespread functional decline. Among these diseases, polyglutamine (polyQ) diseases represent a group of inherited disorders caused by pathological expansions of CAG trinucleotide repeats in specific genes. These expansions lead to the production of proteins with a toxic polyQ tract, which disrupt cellular processes and drive neurodegeneration. Despite extensive research, no effective therapeutics are currently available to delay disease onset or progression. The complexity of cellular landscapes within diseased tissues further complicates efforts to elucidate disease mechanisms, as traditional approaches often obscure the nuanced contributions of diverse cell types and their interactions. As a result, the mechanisms of selective vulnerability and dysfunction remain poorly understood. Here, I investigate the cell-type-specific mechanisms driving the progression of two polyQ diseases, spinocerebellar ataxia type 1 (SCA1) and spinal and bulbar muscular atrophy (SBMA). By employing genetic mouse models and single-nucleus transcriptomic approaches, this work aims to dissect the cellular heterogeneity in diseased tissues, deepen our understanding of disease pathophysiology, and identify potential therapeutic targets.In Chapter 1, I focus on SCA1, a dominantly inherited disorder caused by polyQ-expanded ataxin-1 (ATXN1). Using an oligodendroglia-specific conditional knock-in mouse model (OL-SCA1-cKI), I demonstrate that mutant ataxin-1 expression in oligodendroglia is sufficient to induce hallmark SCA1 pathologies, including motor deficits, hypomyelination, axonal shrinkage, and torpedo formation. Single-nucleus RNA-sequencing (snRNA-seq) reveals subtype-specific transcriptome dysregulation in OLs, providing insights into their contributions to disease pathology and potential therapeutic targets. In Chapter 2, I focus on another polyQ disease, SBMA which is an X-linked recessive disease caused by polyQ-expanded androgen receptor (AR). In collaboration with Dr. Andrew Lieberman’s laboratory at the University of Michigan, we evaluate the therapeutic potential of peripheral administration of AR-targeted antisense oligonucleotides (ASOs) in symptomatic SBMA mice. Utilizing snRNA-seq in spinal cord tissues, I uncover cell-type- and disease-stage-specific gene expression dysregulation across neuronal and glial populations, some of which are partially rescued by ASO therapy. This study sheds light on the cellular complexity of SBMA and explores strategies for targeted therapeutic interventions. Together, my thesis work provides a thorough examination of cell-type-specific mechanisms in SCA1 and SBMA, advancing our understanding of polyQ disease pathogenesis and offering novel therapeutic strategies. By leveraging single-cell transcriptomics and targeted genetic models, this dissertation lays a foundation for future research aimed at mitigating the devastating effects of neurodegenerative disorders.

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