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PolyQ length-dependent metabolic alterations and DNA damage drive human astrocyte dysfunction in Huntington's disease

Lange, Jenny; Gillham, Olivia; Flower, Michael; Ging, Heather; Eaton, Simon; Kapadia, Sneha; Neueder, Andreas; ... Tabrizi, Sarah J; + view all (2023) PolyQ length-dependent metabolic alterations and DNA damage drive human astrocyte dysfunction in Huntington's disease. Progress in Neurobiology , Article 102448. 10.1016/j.pneurobio.2023.102448. Green open access

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Abstract

Huntington's Disease (HD) is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the Huntingtin gene. Astrocyte dysfunction is known to contribute to HD pathology, however our understanding of the molecular pathways involved is limited. Transcriptomic analysis of patient-derived PSC (pluripotent stem cells) astrocyte lines revealed that astrocytes with similar polyQ lengths shared a large number of differentially expressed genes (DEGs). Notably, weighted correlation network analysis (WGCNA) modules from iPSC derived astrocytes showed significant overlap with WGCNA modules from two post-mortem HD cohorts. Further experiments revealed two key elements of astrocyte dysfunction. Firstly, expression of genes linked to astrocyte reactivity, as well as metabolic changes were polyQ length-dependent. Hypermetabolism was observed in shorter polyQ length astrocytes compared to controls, whereas metabolic activity and release of metabolites were significantly reduced in astrocytes with increasing polyQ lengths. Secondly, all HD astrocytes showed increased DNA damage, DNA damage response and upregulation of mismatch repair genes and proteins. Together our study shows for the first time polyQ-dependent phenotypes and functional changes in HD astrocytes providing evidence that increased DNA damage and DNA damage response could contribute to HD astrocyte dysfunction.

Type: Article
Title: PolyQ length-dependent metabolic alterations and DNA damage drive human astrocyte dysfunction in Huntington's disease
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.pneurobio.2023.102448
Publisher version: https://doi.org/10.1016/j.pneurobio.2023.102448
Language: English
Additional information: © 2023 Published by Elsevier Ltd. under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Astrocytes, DNA Damage, Huntington’s Disease, Metabolism, Pluripotent Stem Cells
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10168305
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