Identification of PSMB5 as a genetic modifier of fragile X–associated tremor/ataxia syndrome

• Type of Material: Article
• Authors: Ha Eun Kong, Emory University; Junghwa Lim, Emory University; Alexander Linsalata, University of Michigan Medical School; Yun Kang, Emory University; Indranil Malik, University of Michigan Medical School; Emily Allen, Emory University; Yiqu Cao, Emory University; Lisa Shubeck, Emory University; Rich Johnston, Emory University; Yanting Huang, Emory University; Yanghong Gu, Baylor College of Medicine; Xiangxue Guo, Emory University School of Medicine; Michael Zwick, Emory University; Zhaohui Qin, Emory University; Thomas Wingo, Emory University; Jorge Juncos, Emory University; David L Nelson, Baylor College of Medicine; Michael Epstein, Emory University; David Cutler, Emory University; Peter K Todd, University of Michigan Medical School; Stephanie Sherman, Emory University; Stephen Warren, Emory University; Peng Jin, Emory University
• Language: English
• Date: 2022-05-31
• Publisher: PNAS.
• Publication Version: Final Published Version
• Copyright Statement: © 2022 the Author(s). Published by PNAS.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.2118124119
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 119
• Issue: 22
• Start Page: e2118124119
• End Page: e2118124119
• Keywords: Drosophila melanogaster; fragile X syndrome; Male; premutation; Tremor; PSMB5; Ataxia; Proteasome Endopeptidase Complex; Animals; FXTAS; Fragile X Mental Retardation Protein; Fragile X Syndrome; FMR1; Humans; Disease Models, Animal
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Biostatistics

Abstract

Fragile X–associated tremor/ataxia syndrome (FXTAS) is a debilitating late-onset neurodegenerative disease in premutation carriers of the expanded CGG repeat in FMR1 that presents with a spectrum of neurological manifestations, such as gait ataxia, intention tremor, and parkinsonism [P. J. Hagerman, R. J. Hagerman, Ann. N. Y. Acad. Sci. 1338, 58–70 (2015); S. Jacquemont et al., JAMA 291, 460–469 (2004)]. Here, we performed whole-genome sequencing (WGS) on male premutation carriers (CGG55–200) and prioritized candidate variants to screen for candidate genetic modifiers using a Drosophila model of FXTAS. We found 18 genes that genetically modulate CGG-associated neurotoxicity in Drosophila, such as Prosbeta5 (PSMB5), pAbp (PABPC1L), e(y)1 (TAF9), and CG14231 (OSGEPL1). Among them, knockdown of Prosbeta5 (PSMB5) suppressed CGG-associated neurodegeneration in the fly as well as in N2A cells. Interestingly, an expression quantitative trait locus variant in PSMB5, PSMB5rs11543947-A, was found to be associated with decreased expression of PSMB5 and delayed onset of FXTAS in human FMR1 premutation carriers. Finally, we demonstrate evidence that PSMB5 knockdown results in suppression of CGG neurotoxicity via both the RAN translation and RNA-mediated toxicity mechanisms, thereby presenting a therapeutic strategy for FXTAS.