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

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. models demonstrate progressive storage accumulation, predomi-nantly comprised of subunit C of the mitochondrial ATP synthase (SCMAS),2,3 mirroring what occurs in CLN3 disease patients.4 There-fore, most drug development efforts rely on histopathologic markers of efficacy, including reduction of storage material, reactive astrocyto-sis, and microgliosis.5-7 However, whether these histopathologic changes cause disease, augment the disease process, or are simply harmless epiphenomenon, is unclear.

Automated summary

Neurologic symptoms in lysosomal storage disorders are often caused by neuronal dysfunction rather than storage accumulation, highlighting the importance of understanding the underlying mechanisms for therapy development in these disorders such as CLN3 disease.