The ubiquitin thioesterase YOD1 ameliorates mutant Huntingtin induced pathology in Drosophila

• Published in: Scientific reports Vol. 13; no. 1; pp. 21951 - 13
• Main Authors: Farkas, Anita, Zsindely, Nóra, Nagy, Gábor, Kovács, Levente, Deák, Péter, Bodai, László
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.12.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208; 631/337; 631/378; 692/617; Aggregates; Axonal transport; Drosophila; Gene regulation; Hereditary diseases; Humanities and Social Sciences; Huntingtin; Huntington's disease; Huntingtons disease; Insects; Motor activity; multidisciplinary; Mutants; Neural plasticity; Neurodegenerative diseases; Pathology; Phenotypes; Polyglutamine; Proteasomes; Protein biosynthesis; Protein interaction; Protein synthesis; Protein transport; Science; Science (multidisciplinary); Synaptic transmission; Transcriptomes; Trinucleotide repeat diseases; Ubiquitin thiolesterase
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-49241-8

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.