Recessive ataxias are a heterogeneous group of neurodegenerative diseases. Late-onset ataxias have largely been considered as either milder forms of dominant ataxias or sporadic diseases seemingly not caused by genetic factors. Genotyping of our present cohort, 58 affected cases belonging to 34 families, allowed us to link a form of late-onset cerebellar ataxia (LOCA) with a region on the chromosome 2. Sequencing of genes in the candidate region uncovered mutations in a gene coding for ubiquitin-like protein not previously known to be mutated in a disease. We investigated the effect of the inhibition of the C. elegans homologues on the phenotype. We showed that RNAi silencing in both wild-type N2 and neurosensitive
rrf-3 strains reduced lifespan. The RNAi experience on N2 strain did not activate a number of in vivo stress reporters including
sod-3::GFP,
hsp-4::GFP,
hsp-6::GFP and
hsp-60::GFP. The identification of recessive mutations in a ubiquitin-like gene in LOCA cases suggested that abnormal protein folding also plays a role in this new form of late-onset neurodegenerative disorder so we reasoned that the RNAi gene homologue should affect proteotoxicity. We tested this hypothesis with transgenic worms expressing a polyglutamine-tract of 40 residues fused to YFP. The RNAi accelerated the mean onset of paralysis of these animals compare to control and the appearance of Q40::YFP aggregation puncta. We are now generating a transgenic C. elegans strain for this late-onset ataxia.