Abstract
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.
Highlights
Protein misfolding and aggregation have been implicated in the progression of a number of neurodegenerative disorders including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and prion disorders[1]
It is likely that SNAP-25 adopts abnormal conformations during synaptic activity, which, if not corrected by Cysteine String Protein (CSP) chaperone activity, impair SNARE complex assembly leading to neurodegeneration[20]
Previous work has revealed that both mutant strains exhibit shortened lifespan, age-dependent impairment of locomotion and neurotransmission, and neurodegeneration of sensory neurons coupled with a progressive decline in chemosensory behaviour[25]
Summary
Protein misfolding and aggregation have been implicated in the progression of a number of neurodegenerative disorders including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and prion disorders[1]. Overexpression of SNAP-25 in CSP KO mice was able to rescue the neurodegenerative phenotype[19] These findings have suggested that SNAP-25 is the major client for the chaperone activity of CSP. It is likely that SNAP-25 adopts abnormal conformations during synaptic activity, which, if not corrected by CSP chaperone activity, impair SNARE complex assembly leading to neurodegeneration[20]. CSP-deficient models have been developed in flies and worms[23,24,25,26] These animals exhibit progressive neurodegeneration and reduced lifespan indicating a conserved function for CSP from invertebrates to higher mammals. In the absence of a worm orthologue, human genes containing disease-associated mutations are exogenously, overexpressed in these models[30,31]. C. elegans mutants have been maintained over hundreds of generations which may allow selective pressures to exert effects and reveal compensatory changes in gene expression that might not be observed in mouse KO models that have been maintained for a single generation only
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