GABAergic inhibitory interneurons as a therapeutic target for SCA1

Project: Research project

Project Details


Spinocerebellar ataxia type 1 (SCA1) is caused by a CAG repeat expansion in the ataxin-1 gene that leads to an expanded polyglutamine tract in the Ataxin-1 (ATXN1) protein. SCA1 belongs to a larger family of “proteinopathies” that includes Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. All these disorders begin in mid to late life, but cellular and pathological defects start earlier. In SCA1 for instance the transcriptional changes occurs in cerebellum as early as first week of postnatal period. Moreover, by replenishing these changes (YAPdeltaC/ROR alpha) or by knocking down ATXN1 during early postnatal weeks is enough to mitigate the SCA1 phenotype. Given the importance of this early postnatal period to cerebellar development, and the central role of cerebellar impairment to SCA1, we examined early cerebellar development more closely. We discovered that expanded ATXN1- through transcriptionally up regulating the sonic hedgehog pathway- stimulates the proliferation of postnatal cerebellar stem cells (defined by prominin-1; also called CD133); these stem cells potentially differentiate into GABAergic inhibitory interneurons (basket cells and stellate cells) as opposed to astrocytes. The result is a marked increase in GABAergic inhibition of Purkinje cells in SCA1 mice, as demonstrated by our elecrophysiological sutdies. Analysis of post-mortem material from human SCA1 patients confirms the increased number of GABAergic interneurons. Together these findings inspire the hypothesis that early circuit dysfunction from excessive inhibition in the cerebellum sets the stage for later vulnerability of Purkinje neurons. Hitherto Purkinje cells —that show early dysfunction and degeneration—have been the focus of SCA1 research. Our results suggest that the earliest electrophysiological dysfunctions in PCs is not cell autonomous but stems from outside inhibition from molecular layer interneurons. We hypothesize that by interfering with exaggerated GABAergic inhibition of Purkinje cells, we will be able to mitigate SCA1 pathophysiology. We aim to pursue this hypothesis using both genetic and pharmacological approaches. This proposal tests the validity of our hypothesis; at the same time our studies represent the first comprehensive analysis of this relatively understudied GABAergic interneurons and its involvement in the Purkinje cell toxicity. Our experiments are designed to inspire novel treatments addressing earliest disease alterations so as to have the most clinical impact. Given the growing appreciation that development and degeneration are tightly intertwined in other adult-onset neurodegenerative phenotypes our findings are likely to have broad ramifications.
Effective start/end date3/1/207/1/21


  • National Ataxia Foundation (Agmnt 02/24/20)


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