Identifying astroglia-mediated mechanisms contributing to neuronal vulnerability in spinocerebellar ataxia type 1

The National Institute of Neurological Disorders and Stroke awarded Yale University $149,766 on June 15, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to identify astroglia-mediated mechanisms contributing to neuronal vulnerability in spinocerebellar ataxia type 1.

The research project uses a genetically engineered astroglia-specific SCA1 mouse model (AG-SCA1) to test the hypothesis that astroglia-specific overexpression of mutant ataxin-1 impairs cerebellar purkinje cell synaptic transmission through loss of homeostatic astroglia function. The work employs behavioral, histopathological, and electrophysiological techniques to characterize the impact of astroglia-specific mutant ataxin-1 expression on SCA1-related phenotypes and explores potential distinct effects on regional purkinje cell subtypes. The research addresses the gap that while disease-causative ATXN1 gene mutations are highly expressed in non-neuronal cells—including astroglia, microglia, and oligodendroglia—no disease-modifying treatments currently exist for SCA1 patients and the role of glia in disease pathogenesis remains incompletely understood.

Performance occurs in New Haven, Connecticut. The award runs through May 31, 2028.

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a monogenic neurodegenerative disease caused by a polyglutamine repeat expansion-encoding mutation in the human ATXN1 gene. Like other neurodegenerative diseases in which polygenic variants confer risk, SCA1 exhibits several pathological hallmarks including neuronal vulnerability and protein aggregation. Although posterior purkinje cells (PC) are primarily susceptible in SCA1, the disease- causative ATXN1 gene is also highly expressed in non-neuronal cells - like astroglia, microglia, and oligodendroglia. With no disease-modifying treatments currently available for SCA1 patients, a comprehensive understanding of the role of glia in disease pathogenesis is necessary. Interestingly, previous work has shown that astroglia (AG) undergo pathological changes in the SCA1 knock-in mouse model prior to the onset of PC loss. Our lab has also found that WNT-Β-catenin signaling, a key regulator of cerebellar morphogenesis, is more detrimental to cerebellar health when conditionally activated in AG than in PCS, suggesting that AG may initiate SCA1-like phenotypes in a non-cell autonomous manner. Thus, to further explore the role of AG in SCA1 pathogenesis, we have created an AG-specific SCA1 mouse model, AG-SCA1, in which ATXN182Q is overexpressed in AG using a gfap promoter in a TTA-TRE conditional transgene expression system. Using this model, I propose the central hypothesis that AG-specific overexpression of mutant ataxin-1 will impair PC synaptic transmission through loss of homeostatic AG function and may facilitate distinct effects on regional PC subtypes due to the topographic organization of the cerebellum. Specific aim 1 will identify the impact AG- specific mutant ataxin-1 expression has on SCA1-related phenotypes using behavioral, histopathological, and electrophysiological techniques to explore the non-cell-autonomous contributions of AG toward changes in motor behavior, regional PC structure, and function. Specific aim 2 will investigate the molecular mechanisms by which AG contribute to PC pathogenesis in SCA1 via single-nucleus RNA sequencing of AG-SCA1 and littermate control cerebella. Completion of these aims will allow US to directly assess both the cell- and non-cell autonomous mechanisms by which AG subpopulations, like astrocytes, bergmann glia, and fañanas cells, contribute to changes in PC health in SCA1. The findings identified from this project will not only provide a deeper mechanistic understanding of the role of AG in neurodegeneration but could also prove useful in identifying glial-based targets that promote PC health to prevent SCA1 disease progression. This project will be completed in DR. Janghoo LIM's lab in the yale departments of neuroscience and genetics. The completion of the proposed aims and training plan will further develop the skills I need to become an independent researcher devoted to understanding the mechanisms underlying neurodegeneration.