Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis

摘要: Mutations in the co- chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at synapse fails to explain autophagy-lysosome pathway (ALP) dysfunction cells from AD-ANCL patients. Here, we demonstrate unexpectedly that primary dermal fibroblasts pre-symptomatic mutation carriers recapitulate vitro features found brains patients including auto-fluorescent storage material (AFSM) accumulation, aggregates, increased levels lysosomal proteins and lysosome enzyme activities. AFSM accumulation correlates with aggregation both are susceptible pharmacological modulation ALP function. In addition, endogenous is present lysosome-enriched fractions co-localizes markers soma, neurites synaptic boutons. Overexpression wild-type (WT) decreases lysotracker signal, secreted enzymes SNAP23-mediated exocytosis. WT, mutant aggregated degraded mainly by but this disease-causing exhibits a faster rate degradation. Co-expression WT block fusion autophagosomes/lysosomes. Our data suggest aggregation‐dependent perturbation relevant pathogenic mechanism for supports use or as biomarkers drug screening purposes.