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

根据酵母、苍蝇和小鼠的数据，与年龄相关的神经退行性疾病脊髓小脑共济失调2型（SCA2）和肌萎缩侧索硬化症（ALS 13）可以通过ATXN2的耗竭来预防，因此对患者的临床试验迫在眉睫。迫切的未满足需求是最佳干预年龄和分子进展生物标志物的定义。作为临床前的贡献和阐明的病理机制，我们计划采用一个真实的小鼠模型，致病性突变可以删除在不同年龄的细胞类型特异性的方式。小鼠组织也将用于鉴定作为萎缩和神经保护之间的关键开关的异常ATXN2蛋白相互作用物。所获得的知识将为设计其他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.