Huntington’s disease (HD) is a neurodegenerative disorder caused by a dominant gain-of-function
mutation in the huntingtin gene, resulting in an elongated polyglutamine repeat in
the mutant Huntingtin (mHtt) that mediates aberrant protein interactions. Previous
studies implicated the ubiquitin–proteasome system in HD, suggesting that restoring
cellular proteostasis might be a key element in suppressing pathology. We applied
genetic interaction tests in a Drosophila model to ask whether modulating the levels
of deubiquitinase enzymes affect HD pathology. By testing 32 deubiquitinase genes
we found that overexpression of Yod1 ameliorated all analyzed phenotypes, including
neurodegeneration, motor activity, viability, and longevity. Yod1 did not have a similar
effect in amyloid beta overexpressing flies, suggesting that the observed effects
might be specific to mHtt. Yod1 overexpression did not alter the number of mHtt aggregates
but moderately increased the ratio of larger aggregates. Transcriptome analysis showed
that Yod1 suppressed the transcriptional effects of mHtt and restored the expression
of genes involved in neuronal plasticity, vesicular transport, antimicrobial defense,
and protein synthesis, modifications, and clearance. Furthermore, Yod1 overexpression
in HD flies leads to the upregulation of genes involved in transcriptional regulation
and synaptic transmission, which might be part of a response mechanism to mHtt-induced
stress.