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Neuroinflammation and the role of epigenetic-based therapies for Huntington’s disease management: the new paradigm

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Abstract

Huntington’s disease (HD) is an inherited, autosomal, neurodegenerative ailment that affects the striatum of the brain. Despite its debilitating effect on its patients, there is no proven cure for HD management as of yet. Neuroinflammation, excitotoxicity, and environmental factors have been reported to influence the regulation of gene expression by modifying epigenetic mechanisms. Aside focusing on the etiology, changes in epigenetic mechanisms have become a crucial factor influencing the interaction between HTT protein and epigenetically transcribed genes involved in neuroinflammation and HD. This review presents relevant literature on epigenetics with special emphasis on neuroinflammation and HD. It summarizes pertinent research on the role of neuroinflammation and post-translational modifications of chromatin, including DNA methylation, histone modification, and miRNAs. To achieve this about 1500 articles were reviewed via databases like PubMed, ScienceDirect, Google Scholar, and Web of Science. They were reduced to 534 using MeSH words like ‘epigenetics, neuroinflammation, and HD’ coupled with Boolean operators. Results indicated that major contributing factors to the development of HD such as mitochondrial dysfunction, excitotoxicity, neuroinflammation, and apoptosis are affected by epigenetic alterations. However, the association between neuroinflammation-altered epigenetics and the reported transcriptional changes in HD is unknown. Also, the link between epigenetically dysregulated genomic regions and specific DNA sequences suggests the likelihood that transcription factors, chromatin-remodeling proteins, and enzymes that affect gene expression are all disrupted simultaneously. Hence, therapies that target pathogenic pathways in HD, including neuroinflammation, transcriptional dysregulation, triplet instability, vesicle trafficking dysfunction, and protein degradation, need to be developed.

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Abbreviations

HD:

Huntington’s disease

HTT:

Huntingtin gene

mHtt:

Mutant huntingtin protein

PPAR-GC1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PTM:

Post-translational modifications

DNMTs:

DNA methyltransferase enzymes

TET:

Ten-eleven translocation

7-mG:

7-Methyl guanine

HPLC–UV:

High-performance liquid chromatography–ultraviolet spectroscopy

LC–MS/MS:

Liquid chromatography coupled with tandem mass spectrometry

RFLP:

Restriction fragment length polymorphism

AFLP:

Amplification fragment length polymorphism

HAT:

Histone acetyltransferase

HDAC:

Histone deacetylase

HMT:

Histone methyltransferase

ESET/SETDB1:

ERG-associated protein with SET domain

REST:

Repressor element 1 (RE1) silencing transcription factor

PRMT5:

Arginine dimethyltransferase 5

CREB:

cAMP response element binding

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  1. Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, 151401, Punjab, India

    Pooja Temgire, Richmond Arthur & Puneet Kumar

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  1. Pooja Temgire
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All authors contributed to the study’s inception and design. PT, RA, and PK prepared the materials, collected data, and analysed the results. PT and RA wrote the first draught of the manuscript, and PK provided feedback on prior draughts. The final manuscript was read and approved by all authors.

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Temgire, P., Arthur, R. & Kumar, P. Neuroinflammation and the role of epigenetic-based therapies for Huntington’s disease management: the new paradigm. Inflammopharmacol (2024). https://doi.org/10.1007/s10787-024-01477-0

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