Dataset Information

Ubiquitin-modifying enzymes in Huntington's disease.

ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the N-terminus of the HTT gene. The CAG repeat expansion translates into a polyglutamine expansion in the mutant HTT (mHTT) protein, resulting in intracellular aggregation and neurotoxicity. Lowering the mHTT protein by reducing synthesis or improving degradation would delay or prevent the onset of HD, and the ubiquitin-proteasome system (UPS) could be an important pathway to clear the mHTT proteins prior to aggregation. The UPS is not impaired in HD, and proteasomes can degrade mHTT entirely when HTT is targeted for degradation. However, the mHTT protein is differently ubiquitinated when compared to wild-type HTT (wtHTT), suggesting that the polyQ expansion affects interaction with (de) ubiquitinating enzymes and subsequent targeting for degradation. The soluble mHTT protein is associated with several ubiquitin-modifying enzymes, and various ubiquitin-modifying enzymes have been identified that are linked to Huntington's disease, either by improving mHTT turnover or affecting overall homeostasis. Here we describe their potential mechanism of action toward improved mHTT targeting towards the proteostasis machinery.

SUBMITTER: Sap KA

PROVIDER: S-EPMC10013475 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Ubiquitin-modifying enzymes in Huntington's disease.

Sap Karen A KA Geijtenbeek Karlijne W KW Schipper-Krom Sabine S Guler Arzu Tugce AT Reits Eric A EA

Frontiers in molecular biosciences 20230208

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the N-terminus of the HTT gene. The CAG repeat expansion translates into a polyglutamine expansion in the mutant HTT (mHTT) protein, resulting in intracellular aggregation and neurotoxicity. Lowering the mHTT protein by reducing synthesis or improving degradation would delay or prevent the onset of HD, and the ubiquitin-proteasome system (UPS) could be an important pathway to clear the mHTT proteins pri ...[more]

PMID: 36926679

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Project description:BackgroundPromising disease modifying therapies for Huntington's disease are now entering pivotal trials, raising questions of what patients and families consider successful outcomes. Consistent with an ongoing movement to incorporate patient preferences into the development of new therapies, we conducted a pilot study to assess Huntington's disease community views on emerging DMTs to assist in planning large-scale studies of patient preferences.MethodsSemi-structured interviews were conducted with members of the Huntington's community (manifest disease, at-risk, and family/caregivers). Participants were asked which symptoms they believed should be targeted with novel treatments, as well as potential benefits and tradeoffs of delaying symptom onset versus prolonging late-stage disease.ResultsParticipants (N = 14) emphasized the need for treatments improving cognitive and/or behavioral symptoms. Many wanted treatments that delayed symptom onset up to 5-10 years, though some considered shorter delays acceptable due to potential value in advancing research to help future generations. Concern regarding potential for prolonging later-stage disease was variable, with some participants uncertain if they would want a treatment that delayed onset but prolonged later-stage disease. Others stated that any delay in onset would be desirable, regardless of potential prolongation of later stage disease.DiscussionThis study demonstrates a breadth of opinions among the Huntington's disease community surrounding both the benefits and complex tradeoffs that might occur with disease modifying treatments. These preliminary findings will inform future large-scale studies of attitudes toward disease modifying treatments, which may ultimately guide the design and outcome measure selection for clinical trials.HighlightsIn-depth interviews with the Huntington's disease community were used to explore patient and family preferences regarding potential disease modifying therapies. Many wanted symptom delay of 5-10 years, though some considered shorter delays acceptable for altruistic reasons. Opinions on trade-offs varied, suggesting larger preference studies are needed to inform trial design.

Dataset Information

Ubiquitin-modifying enzymes in Huntington's disease.

Publications

Ubiquitin-modifying enzymes in Huntington's disease.

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