Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Interdepartmental Neuroscience Program
First Advisor
Lim, Janghoo
Abstract
Neurodegenerative disorders are highly complex, progressive disorders often involving interactions of multiple cell types, disease-causing genes and pathways, and brain regions. For the majority of neurodegenerative disorders, no effective therapeutics are currently available to slow disease onset or progression, and the mechanisms underlying the degeneration of specific cellular populations remain largely unknown. Here, we use spinocerebellar ataxia type 1 (SCA1) as a model to investigate the impact of the disease-causing gene, ATAXIN-1 (ATXN1), in diverse cell types and brain regions. We identify region-specific differences in disease signatures, and investigate the mechanistic contribution of glia, specifically astrocytes, towards SCA1 pathology and progression, in an effort to advance our understanding of the mechanisms underlying disease progression and potentially help identify novel therapeutic targets for future development. In the first chapter, I investigate region-specific disease signatures in a knock-in mouse model of SCA1 by comparing aggregate composition, transcriptomic signatures, and astro- and micro-gliosis across the SCA1 cortex and cerebellum. Here, I identify novel pathology in the SCA1 cortex, and identify region-specific differences in kinase regulation and gliosis across the cerebellum and cortex in SCA1. In the second chapter, we identify a signaling pathway, Wnt-β-catenin signaling, that is progressively upregulated in diverse cell types in SCA1. We provide a novel mechanism in which the SCA1 disease-causing protein, Ataxin-1, positively regulates Wnt-β-catenin signaling in a polyglutamine-dependent manner in various cell types. We use in vivo conditional mouse genetics and in vitro co-culture systems to validate the functional importance of this activation in neuronal and glial populations, specifically Purkinje cells and astrocytes/Bergmann glia, respectively. We find that activation of Wnt-β-catenin signaling is more detrimental in astrocytes than in Purkinje cells, underscoring an important role of Bergmann glia in SCA1 pathogenesis. In the third chapter, I investigate the role of mutant ataxin-1 expression in astrocytes towards SCA1 disease progression using conditional mouse genetics. We generate an astrocyte-specific mouse model of SCA1, and find that mutant ataxin-1 expression in astrocytes alone is sufficient to induce adult-onset, progressive behavioral deficits, glial dysfunction, and non-cell autonomous cerebellar atrophy and molecular layer thinning. Interestingly, we observe that the posterior cerebellum is more vulnerable to astrocyte-specific mutant ataxin-1 expression, similar to other SCA1 mouse models and human patients. Together, these data identify novel mechanisms in which diverse brain regions, signaling pathways, and cell types contribute towards SCA1 pathogenesis and neurodegeneration.
Recommended Citation
Luttik, Kimberly Petra, "Identifying Cellular and Molecular Mechanisms Contributing Towards Neuronal Vulnerability in Spinocerebellar Ataxia Type 1" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1201.
https://elischolar.library.yale.edu/gsas_dissertations/1201
