Poly ADP-ribose signaling is dysregulated in Huntington disease

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 40; p. 1
• Main Authors: Maiuri, Tamara, Bazan, Carlos Barba, Harding, Rachel J, Begeja, Nola, Kam, Tae-In, Byrne, Lauren M, Rodrigues, Filipe B, Warner, Monica M, Neuman, Kaitlyn, Mansoor, Muqtasid, Badiee, Mohsen, Dasovich, Morgan, Wang, Keona, Thompson, Leslie M, Leung, Anthony K L, Andres, Sara N, Wild, Edward J, Dawson, Ted M, Dawson, Valina L, Arrowsmith, Cheryl H, Truant, Ray
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 01.10.2024
• Subjects: Adenine; Adenosine diphosphate; Ataxia; Atomic force microscopy; Binding; Cerebellar ataxia; Cerebellum; Cerebrospinal fluid; Chromosomes; Cytosine; Damage detection; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Fluorescence polarization; Genome-wide association studies; Huntingtin; Huntington's disease; Huntingtons disease; Mitochondrial DNA; Molecular modelling; Mutants; Neurodegenerative diseases; Pluripotency; Poly(ADP-ribose) polymerase; Polyglutamine diseases; Proteins; Ribose; Stem cells; Trinucleotide repeat diseases; Trinucleotide repeats
• ISSN: 0027-8424; 1091-6490

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin (HTT) 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.