A model of neuronal ceroid lipofuscinosis reveals a hypermorphic gain of function mechanism.

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of by expressing mutant human CSPα (hCSPα) in neurons. Similar to patients, mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated phenotypes. Taken together, we suggest that alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.