Hdac4 Interactions in Huntington's Disease Viewed Through the Prism of Multiomics

Federspiel, Joel D.; Greco, Todd M.; Lum, Krystal K.; Cristea, Ileana M.

doi:10.1074/mcp.ra118.001253

Cited by 29 publications

(23 citation statements)

References 80 publications

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“…Characterization of interactome of endogenous HDAC4 in brains of HD mouse models revealed interaction of HDAC4 with Wiskott-Aldrich Syndrome Protein and SCAR Homolog (WASH) complex. This study confirmed the role of HDAC4 in progression of HD (Federspiel et al, 2019).…”

Section: Huntington Diseasesupporting

confidence: 85%

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

2020

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Histone deacetylases (HADC) are the enzymes that remove acetyl group from lysine residue of histones and non-histone proteins and regulate the process of transcription by binding to transcription factors and regulating fundamental cellular process such as cellular proliferation, differentiation and development. In neurodegenerative diseases, the histone acetylation homeostasis is greatly impaired, shifting towards a state of hypoacetylation. The histone hyperacetylation produced by direct inhibition of HDACs leads to neuroprotective actions. This review attempts to elaborate on role of small molecule inhibitors of HDACs on neuronal differentiation and throws light on the potential of HDAC inhibitors as therapeutic agents for treatment of neurodegenerative diseases. The role of HDACs in neuronal cellular and disease models and their modulation with HDAC inhibitors are also discussed. Significance of these HDAC inhibitors has been reviewed on the process of neuronal differentiation, neurite outgrowth and neuroprotection regarding their potential therapeutic application for treatment of neurodegenerative diseases.

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Section: Huntington Diseasesupporting

confidence: 85%

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

2020

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“…In a previous study, end-stage disease occurred much earlier, and the range of neurological phenotypes was more extensive in R6/2 mice with aggregate pathology in both the nucleus and cytoplasm, as compared to those with comparable aggregation occurring in the nucleus only ( Benn et al , 2005 ). In keeping with this, heterozygosity for HDAC4, a cytoplasmic protein that interacts with HTT ( Mielcarek et al , 2013 ; Federspiel et al , 2019 ), delayed aggregation in the cytoplasm, improved behavioural phenotypes, and delayed end-stage disease in R6/2 mice, whilst the levels of nuclear aggregation and transcriptional dysregulation were unchanged ( Mielcarek et al , 2013 ).…”

Section: Discussionmentioning

confidence: 71%

Subcellular Localization And Formation Of Huntingtin Aggregates Correlates With Symptom Onset And Progression In A Huntington’S Disease Model

Landles

Milton

Ali

et al. 2020

Brain Communications

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Huntington’s disease is caused by the expansion of a CAG repeat within exon 1 of the HTT gene, which is unstable, leading to further expansion, the extent of which is brain region and peripheral tissue specific. The identification of DNA repair genes as genetic modifiers of Huntington’s disease, that were known to abrogate somatic instability in Huntington’s disease mouse models, demonstrated that somatic CAG expansion is central to disease pathogenesis, and that the CAG repeat threshold for pathogenesis in specific brain cells might not be known. We have previously shown that the HTT gene is incompletely spliced generating a small transcript that encodes the highly pathogenic exon 1 HTT protein. The longer the CAG repeat, the more of this toxic fragment is generated, providing a pathogenic consequence for somatic expansion. Here, we have used the R6/2 mouse model to investigate the molecular and behavioural consequences of expressing exon 1 HTT with 90 CAGs, a mutation that causes juvenile Huntington’s disease, compared to R6/2 mice carrying ∼200 CAGs, a repeat expansion of a size rarely found in Huntington’s disease patient’s blood, but which has been detected in post mortem brains as a consequence of somatic CAG repeat expansion. We show that nuclear aggregation occurred earlier in R6/2(CAG)90 mice and that this correlated with the onset of transcriptional dysregulation in these lines. Whereas in R6/2(CAG)200 mice, cytoplasmic aggregates accumulated rapidly and closely tracked with the progression of behavioural phenotypes and with end-stage disease. We find that aggregate species formed in the R6/2(CAG)90 brains have different properties to those in the R6/2(CAG)200 mice. Within the nucleus, they retain a diffuse punctate appearance throughout the course of the disease, can be partially solubilised by detergents and have a greater seeding potential in young mice. In contrast, aggregates from R6/2(CAG)200 brains polymerise into larger structures that appear as inclusion bodies. These data emphasise that a subcellular analysis, using multiple complementary approaches, must be undertaken in order to draw any conclusions about the relationship between HTT aggregation and the onset and progression of disease phenotypes.

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“…protein function. Federspiel et al (11) used a multi-omics approach to uncover the function of histone deacetylase 4 (Hdac4) in the context of Huntington's disease (HD) progression. The authors characterized the interactomes of endogenous Hdac4 in the brains of HD mouse models with wild type and mutant forms of the huntingtin (Htt) gene at both presymptomatic and symptomatic ages.…”

mentioning

confidence: 99%

Proteomics Is Not an Island: Multi-omics Integration Is the Key to Understanding Biological Systems

Zhang

Küster

2019

Molecular & Cellular Proteomics

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Hdac4 Interactions in Huntington's Disease Viewed Through the Prism of Multiomics

Cited by 29 publications

References 80 publications

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

Subcellular Localization And Formation Of Huntingtin Aggregates Correlates With Symptom Onset And Progression In A Huntington’S Disease Model

Proteomics Is Not an Island: Multi-omics Integration Is the Key to Understanding Biological Systems

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