Dataset Information

Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington's Disease Pathology.

ABSTRACT: Huntington's disease (HD) is a lethal autosomal dominant neurodegenerative disorder resulting from a CAG repeat expansion in the huntingtin (HTT) gene. The product of translation of this gene is a highly aggregation-prone protein containing a polyglutamine tract >35 repeats (mHTT) that has been shown to colocalize with histone deacetylase 4 (HDAC4) in cytoplasmic inclusions in HD mouse models. Genetic reduction of HDAC4 in an HD mouse model resulted in delayed aggregation of mHTT, along with amelioration of neurological phenotypes and extended lifespan. To further investigate the role of HDAC4 in cellular models of HD, we have developed bifunctional degraders of the protein and report the first potent and selective degraders of HDAC4 that show an effect in multiple cell lines, including HD mouse model-derived cortical neurons. These degraders act via the ubiquitin-proteasomal pathway and selectively degrade HDAC4 over other class IIa HDAC isoforms (HDAC5, HDAC7, and HDAC9).

SUBMITTER: Macabuag N

PROVIDER: S-EPMC9512014 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington's Disease Pathology.

Macabuag Natsuko N Esmieu William W Breccia Perla P Jarvis Rebecca R Blackaby Wesley W Lazari Ovadia O Urbonas Liudvikas L Eznarriaga Maria M Williams Rachel R Strijbosch Annelieke A Van de Bospoort Rhea R Matthews Kim K Clissold Cole C Ladduwahetty Tammy T Vater Huw H Heaphy Patrick P Stafford Douglas G DG Wang Hong-Jun HJ Mangette John E JE McAllister George G Beaumont Vahri V Vogt Thomas F TF Wilkinson Hilary A HA Doherty Elizabeth M EM Dominguez Celia C

Journal of medicinal chemistry 20220913 18

Huntington's disease (HD) is a lethal autosomal dominant neurodegenerative disorder resulting from a CAG repeat expansion in the huntingtin (<i>HTT</i>) gene. The product of translation of this gene is a highly aggregation-prone protein containing a polyglutamine tract >35 repeats (mHTT) that has been shown to colocalize with histone deacetylase 4 (HDAC4) in cytoplasmic inclusions in HD mouse models. Genetic reduction of HDAC4 in an HD mouse model resulted in delayed aggregation of mHTT, along w ...[more]

PMID: 36098485

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Project description:Huntington's disease (HD) is a monogenic disorder, driven by the expansion of a trinucleotide (CAG) repeat within the huntingtin (Htt) gene and culminating in neuronal degeneration in the brain, predominantly in the striatum and cortex. Histone deacetylase 4 (Hdac4) was previously found to contribute to the disease progression, providing a potential therapeutic target. Hdac4 knockdown reduced accumulation of misfolded Htt protein and improved HD phenotypes. However, the underlying mechanism remains unclear, given its independence on deacetylase activity and the predominant cytoplasmic Hdac4 localization in the brain. Here, we undertook a multiomics approach to uncover the function of Hdac4 in the context of HD pathogenesis. We characterized the interactome of endogenous Hdac4 in brains of HD mouse models. Alterations in interactions were investigated in response to Htt polyQ length, comparing mice with normal (Q20) and disease (Q140) Htt, at both pre- and post-symptomatic ages (2 and 10 months, respectively). Parallel analyses for Hdac5, a related class IIa Hdac, highlighted the unique interaction network established by Hdac4. To validate and distinguish interactions specifically enhanced in an HD-vulnerable brain region, we next characterized endogenous Hdac4 interactions in dissected striata from this HD mouse series. Hdac4 associations were polyQ-dependent in the striatum, but not in the whole brain, particularly in symptomatic mice. Hdac5 interactions did not exhibit polyQ dependence. To identify which Hdac4 interactions and functions could participate in HD pathogenesis, we integrated our interactome with proteome and transcriptome data sets generated from the striata. We discovered an overlap in enriched functional classes with the Hdac4 interactome, particularly in vesicular trafficking and synaptic functions, and we further validated the Hdac4 interaction with the Wiskott-Aldrich Syndrome Protein and SCAR Homolog (WASH) complex. This study expands the knowledge of Hdac4 regulation and functions in HD, adding to the understanding of the molecular underpinning of HD phenotypes.

Project description:BackgroundRecent findings suggest that individuals with Huntington's disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear.ObjectivesTo evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments.MethodsTwenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment.ResultsCompared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P < 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P < 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test-retest reliability [ICC: 0.61-0.99] for individuals with presymptomatic and prodromal HD and healthy controls.ConclusionsIndividuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls.

Dataset Information

Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington's Disease Pathology.

Publications

Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington's Disease Pathology.

Similar Datasets

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