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

根据酵母、苍蝇和小鼠的数据，年龄相关的神经退行性疾病脊髓小脑性共济失调2型（SCA2）和肌萎缩侧索硬化症（ALS13）可以通过消耗ATXN2来预防，因此针对患者的临床试验迫在眉睫。尚未满足的迫切需求是干预的最佳年龄和分子进展生物标志物的定义。作为临床前贡献和阐明病理机制，我们计划采用一种真实的小鼠模型，其中致病性突变可以在不同年龄以细胞类型特异性的方式删除。小鼠组织还将用于鉴定异常的ATXN2蛋白相互作用物，该相互作用物在萎缩和神经保护之间充当关键开关。所获得的知识将为设计更多的预防性治疗方法提供基础。

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.