Primary fibroblasts from CSP? mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis.

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

SUBMITTER: Benitez BA 

PROVIDER: S-EPMC5524943 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature