PDF(Pubmed)
Abstract：
Although neurologic symptoms occur in two-thirds of lysosomal storage disorders (LSDs), for most we do not understand the mechanisms underlying brain dysfunction. A major unanswered question is if the pathogenic hallmark of LSDs, storage accumulation, induces functional defects directly or is a disease bystander. Also, for most LSDs we do not know the impact of loss of function in individual cell types. Understanding these critical questions are essential to therapy development. Here, we determine the impact of genetic rescue in distinct cell types on neural circuit dysfunction in CLN3 disease, the most common pediatric dementia and a paradigmatic neurodegenerative LSD. We restored Cln3 expression via AAV-mediated gene delivery and conditional genetic rescue in a CLN3 disease mouse model. Surprisingly, we found that low-level rescue of Cln3 expression in neurons alone normalized clinically relevant electrophysiologic markers of network dysfunction, despite the presence of substantial residual histopathology, in contrast to restoring expression in astrocytes. Thus, loss of CLN3 function in neurons, not storage accumulation, underlies neurologic dysfunction in CLN3 disease. This impliesies that storage clearance may be an inappropriate target for therapy development and an ineffectual biomarker.
摘要：
尽管神经系统症状发生在三分之二的溶酶体贮积症（LSD）中，对于大多数人来说，我们不了解大脑功能障碍的潜在机制。一个主要的悬而未决的问题是，如果LSD的致病标志，储存积累，直接诱导功能缺陷或者是疾病旁观者。此外，对于大多数LSD，我们不知道单个细胞类型功能丧失的影响。了解这些关键问题对于治疗发展至关重要。这里,我们确定了不同细胞类型的遗传拯救对CLN3疾病中神经回路功能障碍的影响，最常见的小儿痴呆和典型的神经退行性LSD。我们在CLN3疾病小鼠模型中通过AAV介导的基因递送和条件遗传拯救恢复了Cln3表达。令人惊讶的是,我们发现，在神经元中低水平挽救的Cln3表达使网络功能障碍的临床相关电生理标志物正常化，尽管存在大量残留的组织病理学，与星形胶质细胞中恢复表达相反。因此，神经元中CLN3功能的丧失，不是储存积累，CLN3疾病的神经系统功能障碍。这暗示了储存清除可能是治疗开发的不适当目标和无效的生物标志物。
