Reversibility of SCA2/ALS13: Contribution of cell types, in conditional mice

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The age-associated neurodegenerative disorders Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis (ALS13) can be prevented by depletion of ATXN2, according to data in yeast, flies and mice, so clinical trials for patients are imminent. Urgent unmet needs are the definition of the best age for intervention and of molecular progression biomarkers. As preclinical contribution and to elucidate the pathomechanism, we plan to employ an authentic mouse model where the pathogenic mutation can be deleted in cell-type-specific manner at diverse ages. Mouse tissue will be used also to identify the aberrant ATXN2 protein interactors that act as key switches between atrophy and neuroprotection. The knowledge gained will provide a basis to design additional preventive treatment approaches.