The ubiquitin thioesterase YOD1 ameliorates mutant Huntingtin induced pathology in Drosophila
Creators
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1.
University of Szeged
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2.
California Institute of Technology
Abstract
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.
Copyright and License
© Te Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Acknowledgement
The authors thank Zita Kóra for technical assistance. We thank Prof. J. Lawrence Marsh (University of California, Irvine) for providing Drosophila stocks.
Funding
This research was funded by National Research, Development and Innovation Office [HU] grants GINOP-2.3.2-15-2016-00032 and GINOP-2.3.2-15-2016-00034. L.B. was supported by the János Bolyai Research Scholarship (BO/00522/19/8) of the Hungarian Academy of Sciences and by the ÚNKP-21-5-SZTE-574—New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. Open access publishing costs were covered by the University of Szeged Open Access Fund grant 6303. The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Contributions
A.F. performed Drosophila experiments and participated in the acquisition, analysis, and interpretation of data, and reviewing the manuscript. N.Z.: performed RNA-seq experiments, participated in the interpretation of data, and reviewed the manuscript., G.N.: performed bioinformatic and statistical analysis of data, and reviewed the manuscript, L.K. performed Drosophila experiments and revised the manuscript, P.D. participated in experiment design, interpretation of data, and reviewing the manuscript., L.B. participated in the study conception and design of experiments, statistical analysis, and interpretation of data, and wrote the manuscript draft. All authors read and approved the final manuscript.
Data Availability
RNA-seq sequence files generated and analyzed during the current study are available in the NCBI Sequence Read Archive repository under accession PRJNA991110 (https://www.ncbi.nlm.nih.gov/sra/PRJNA991110). Other datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Conflict of Interest
The authors declare no competing interests.
Files
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Additional details
Identifiers
- PMCID
- PMC10713573
Related works
Funding
- National Research, Development and Innovation Office [HU]
- GINOP-2.3.2-15-2016-00032
- Hungarian Academy of Sciences
- BO/00522/19/8
- Ministry for Innovation and Technology
- ÚNKP-21-5-SZTE-574
- University of Szeged Open Access Fund
- 6303