Atxn2-CAG100-Knock-In Model for Spinocerebellar Ataxia Type 2

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Among the neurodegenerative disorders caused by poly-glutamine domain expansions, Spinocerebellar Ataxia type 2 (SCA2), Amyotrophic Lateral Sclerosis (ALS13) and LevoDopa-responsive Parkinson were reported to be triggered by mutant Ataxin-2, a RNA-binding protein. To model these diseases in mouse, after the published characterization of a 42-glutamine-ATXN2-knock-in we now successfully generated a 100-glutamine-ATXN2-knock-in. Here, we propose to use the cerebellar and brainstem / spinal cord tissue from aged mice to elucidate the progressive neurodegeneration through molecular studies, interaction analyses, calcium-imaging, electrophysiology, histology and behaviour tests. We also plan to establish organotypic cultures of cerebellum to dissect the role of crucial molecules and attempt rescue experiments. Overall, this approach will document tissue-specific effects of expanded ATXN2 on RNAs and proteins, thus identifying molecular and functional biomarkers of pathology.