Exploring the role of high-mobility group box 1 (HMGB1) protein in the pathogenesis of Huntington’s disease.

Publication date: Feb 08, 2020

Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by an increased and unstable CAG DNA expansion in the Huntingtin (HTT) gene, resulting in an elongated polyglutamine tract in huntingtin protein. Despite its monogenic cause, HD pathogenesis remains elusive and without any approved disease-modifying therapy as yet. A growing body of evidence highlights the emerging role of high-mobility group box 1 (HMGB1) protein in HD pathology. HMGB1, being a nuclear protein, is primarily implicated in DNA repair, but it can also translocate to the cytoplasm and participate into numerous cellular functions. Cytoplasmic HMGB1 was shown to directly interact with huntingtin under oxidative stress conditions and induce its nuclear translocation, a key process in the HD pathogenic cascade. Nuclear HMGB1 acting as a co-factor of ataxia telangiectasia mutated and base excision repair (BER) complexes can exert dual roles in CAG repeat instability and affect the final DNA repair outcome. HMGB1 can inhibit mutant huntingtin aggregation, protecting against polyglutamine-induced neurotoxicity and acting as a chaperon-like molecule, possibly via autophagy regulation. In addition, HMGB1 being a RAGE and TLR-2, TLR-3, and TLR-4 ligand may further contribute to HD pathogenesis by triggering neuroinflammation and apoptosis. Furthermore, HMGB1 participates at the unfolded protein response (UPR) system and can induce protein degradation and apoptosis associated with HD. In this review, we discuss the multiple role of HMGB1 in HD pathology, providing mechanistic insights that could direct future studies towards the development of targeted therapeutic approaches.

Angelopoulou, E., Paudel, Y.N., and Piperi, C. Exploring the role of high-mobility group box 1 (HMGB1) protein in the pathogenesis of Huntington’s disease. 06923. 2020 J Mol Med (Berl).

Concepts Keywords
Apoptosis Apoptosis
Ataxia Telangiectasia HTT
Autophagy Neuroinflammation
Autosomal Dominant TOX
Base Excision Repair Apoptosis
BER Neurodegeneration
Chaperon High-mobility group
Cytoplasm RAGE
Gene Huntingtin
Huntingtin HMGB1
Huntingtin Protein Transcription factors
Huntington Branches of biology
Interact Disease
Neurodegenerative Disorder
Oxidative Stress


Type Source Name
disease MESH oxidative stress
pathway REACTOME DNA Repair
disease MESH pathology
disease MESH development
pathway KEGG Apoptosis
pathway KEGG Autophagy
pathway KEGG Base excision repair
disease MESH ataxia telangiectasia
disease MESH neurodegenerative disorder


Original Article

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