Expression profile of a Caenorhabditis elegans model of adult neuronal ceroid lipofuscinosis reveals down regulation of ubiquitin E3 ligase components.

Cysteine string protein (CSP) is a chaperone of the Dnaj/Hsp40 family of proteins and is essential for synaptic maintenance. Mutations in the human gene encoding CSP, DNAJC5, cause adult neuronal ceroid lipofucinosis (ANCL) which is characterised by progressive dementia, movement disorders, seizures and premature death. CSP null models in mice, flies and worms have been shown to also exhibit similar neurodegenerative phenotypes. Here we have explored the mechanisms underlying ANCL disease progression using Caenorhaditis elegans mutant strains of dnj-14, the worm orthologue of DNAJC5. Transcriptional profiling of these mutants compared to control strains revealed a broad down-regulation of ubiquitin proteasome system (UPS)-related genes, in particular, components of multimeric RING E3 ubiquitin ligases including F-Box, SKR and BTB proteins. These data were supported by the observation that dnj-14 mutant worm strains expressing a GFP-tagged ubiquitin fusion degradation substrate exhibited decreased ubiquitylated protein degradation. The results indicate that disruption of an essential synaptic chaperone leads to changes in expression levels of UPS-related proteins which has a knock-on effect on overall protein degradation in C. elegans. The specific over-representation of E3 ubiquitin ligase components revealed in our study, suggests that proteins and complexes upstream of the proteasome itself may be beneficial therapeutic targets.