Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation

摘要: 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 pathogenic hallmark LSDs, accumulation, induces functional defects directly or a disease bystander. Also, LSDs know impact loss-of-function individual cell types. Understanding these critical questions are essential to therapy development. Here, determined genetic rescue distinct types on neural circuit dysfunction CLN3 disease, common pediatric dementia and representative LSD. We restored Cln3 expression via AAV-mediated gene delivery conditional mouse model. Surprisingly, found that low-level neurons alone normalized clinically-relevant electrophysiologic markers network dysfunction, despite presence substantial residual histopathology, contrast restoring astrocytes. Thus loss function neurons, underlies implying clearance may be an inappropriate target development ineffectual biomarker.