Poly ADP-ribose signaling is dysregulated in Huntington disease

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the <i>Huntingtin</i> (<i>HTT</i>) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-09-27
DOI
https://doi.org/10.1073/pnas.2318098121
Citations
15
Primary Topic
PARP inhibition in cancer therapy
Type
article
Field-Weighted Citation Impact
4.24

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article

Poly ADP-ribose signaling is dysregulated in Huntington disease

Sara N. Andres, C.H. Arrowsmith, Edward J. Wild, Lauren M. Byrne et al.
15 citations
Proceedings of the National Academy of Sciences
PARP inhibition in cancer therapy
4.24
article

Poly ADP-ribose signaling is dysregulated in Huntington disease

Sara N. Andres, C.H. Arrowsmith, Edward J. Wild, Lauren M. Byrne, Kaitlyn Neuman, Ted M. Dawson, Filipe B. Rodrigues, Valina L. Dawson, Tamara Maiuri, Ray Truant, Anthony K. L. Leung, Leslie Michels Thompson, Rachel Harding, Muqtasid Mansoor, Mohsen Badiee, Keona Q. Wang, Carlos Barba Bazan, Nola Begeja, Tae‐In Kam, Morgan Dasovich, Monica M Warner
article en
15 citations

Abstract

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the <i>Huntingtin</i> (<i>HTT</i>) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies.

Proceedings of the National Academy of SciencesVol. 121(40)
3M (United States) (US), Johns Hopkins University (US), Queen Mary University of London (GB), University of Toronto (CA), University of California, Irvine (US), Johns Hopkins Medicine (US), Princess Margaret Cancer Centre (CA), Structural Genomics Consortium (CA), Stem Cell Institute (PA), University College London (GB), McMaster University (CA)
Bristol-Myers Squibb, Pfizer, Bayer, CHDI Foundation, F. Hoffmann-La Roche, Johns Hopkins University, McGill University, Genome Canada, McMaster University, Merck KGaA, Ontario Genomics, European Federation of Pharmaceutical Industries and Associations, Ontario Genomics Institute, University College London, University of Toronto, Krembil Foundation, National Institutes of Health, Genentech, Johns Hopkins Bloomberg School of Public Health, University of California, Irvine, School of Medicine, Johns Hopkins University, Canadian Institutes of Health Research, Medical Research Council, National Institute of Neurological Disorders and Stroke
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Openalex Percentile: Top 4%
PARP inhibition in cancer therapy
4.24
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