The C. elegans cysteine-string protein homologue, DNJ-14, is dispensable for neuromuscular junction maintenance across ageing

Abstract

Maintenance of synaptic function across ageing is vital in sustaining cognitive function. Synaptic dysfunction is a key part of the pathophysiology of a number of neurodegenerative diseases. The synaptic co-chaperone, cysteine-string protein (CSP), is important for synaptic maintenance and function in Drosophila, mice and humans, and disruption of CSP results in synaptic degeneration. We sought to characterise synaptic ageing in Caenorhabditis elegans upon genetic disruption of CSP. To do this, we focused on the worms' neuromuscular junctions, which are the best characterised synapse. CSP mutant worms did not display reduced lifespan or any neuromuscular-dependent behavioural deficits across ageing. Pharmacological interrogation of the neuromuscular synapse of CSP mutant animals showed no sign of synaptic dysfunction even at advanced age. Lastly, patch clamp analysis of neuromuscular transmission across ageing in wild-type and CSP mutant animals revealed no obvious CSP-dependent deficits. Electrophysiological spontaneous postsynaptic current analysis reinforced pharmacological observations that the C. elegans neuromuscular synapse increases in strength during early ageing and remains relatively intact in old, immotile worms. Taken together, this study shows that surprisingly, despite disruption of CSP in other animals having severe synaptic phenotypes, CSP does not seem to be important for maintenance of the neuromuscular junction across ageing in C. elegans.

Modeling neurodegeneration in Caenorhabditis elegans

“…A study of the neurotoxic selectivity of perfluorooctane sulfonate, a chemical widely used in industry, showed that exposure causes dopaminergic neuron deficits and, through the use of aldicarb, found that this was independent of acetylcholine function ( Sammi et al, 2019 ). In another study, an aldicarb-based assay showed that DNJ-14, a worm homolog of the human cysteine-string protein (DNAJC5), a co-chaperone necessary for synaptic maintenance, was not required for neuromuscular transmission in aging ( Mulcahy et al, 2019 ). Conversely, in an ALS/FTD model, Vaccaro et al (2012a , b) showed that transgenic worms expressing either mutant or wild-type human TDP-43 and FUS differed in their response to aldicarb, with the mutants exhibiting hypersensitivity to paralysis.…”

Tissue distribution of cysteine string protein/DNAJC5 in C. elegans analysed by CRISPR/Cas9-mediated tagging of endogenous DNJ-14

“…CSP’s function in C. elegans has been explored by mutational analyses of its orthologue dnj-14 (Barker et al 2023 ; Chen et al 2015 ; Kashyap et al 2014 ; McCue et al 2015 ; Mulcahy et al 2019 ). However, it remains unknown which worm cells/tissues express DNJ-14 protein and hence may contribute to dnj-14 mutant phenotypes.…”