Journal
CURRENT OPINION IN NEUROBIOLOGY
Volume 72, Issue -, Pages 39-47Publisher
CURRENT BIOLOGY LTD
DOI: 10.1016/j.conb.2021.07.001
Keywords
Polyglutamine; Repeat expansion; CAG repeat; Huntington's disease; Spinal and bulbar muscular atrophy
Categories
Funding
- CHDI Foundation
- Rosetrees Trust
- Vertex Pharmaceuticals
- UK Medical Research Council (MRC)
- Wellcome Trust [200181/Z/15/Z]
- UK Dementia Research Institute (DRI) from DRI Ltd.
- UK MRC
- Alzheimer's Society
- Alzheimer's Research UK
- Medical Research Council
- UK Dementia Research Institute
- Wellcome Trust [200181/Z/15/Z] Funding Source: Wellcome Trust
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Polyglutamine diseases, including a group of CAG trinucleotide expansion disorders, involve DNA repair genes in disease pathogenesis, with autophagy activation as a potential therapeutic target.
Polyglutamine diseases are a collection of nine CAG trinucleotide expansion disorders, presenting with a spectrum of neurological and clinical phenotypes. Recent human, mouse and cell studies of Huntington's disease have highlighted the role of DNA repair genes in somatic expansion of the CAG repeat region, modifying disease pathogenesis. Incomplete splicing of the HTT gene has also been shown to occur in humans, with the resulting exon 1 fragment most probably contributing to the Huntington's disease phenotype. In the spinocerebellar ataxias, studies have converged on transcriptional dysregulation of ion channels as a key disease modifier. In addition, advances have been made in understanding how increased levels of toxic, polyglutamine-expanded proteins can arise in the spinocerebellar ataxias through post-transcriptional and-translational modifications and autophagic mechanisms. Recent studies in spinal and bulbar muscular atrophy implicate similar pathogenic pathways to the more common polyglutamine diseases, highlighting autophagy stimulation as a potential therapeutic target. Finally, the therapeutic use of antisense oligonucleotides in several polyglutamine diseases has shown preclinical benefits and serves as potential future therapies in humans.
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