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

Autor:	Kong HE; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Lim J; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Linsalata A; Department of Neurology, University of Michigan, Veteran's Affairs Medical Center, Ann Arbor, MI 48109., Kang Y; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Malik I; Department of Neurology, University of Michigan, Veteran's Affairs Medical Center, Ann Arbor, MI 48109., Allen EG; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Cao Y; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Shubeck L; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Johnston R; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Huang Y; Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322., Gu Y; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030., Guo X; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Zwick ME; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Qin Z; Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322., Wingo TS; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322.; Department of Neurology, School of Medicine, Emory University, Atlanta, GA 30322., Juncos J; Department of Neurology, School of Medicine, Emory University, Atlanta, GA 30322., Nelson DL; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030., Epstein MP; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Cutler DJ; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Todd PK; Department of Neurology, University of Michigan, Veteran's Affairs Medical Center, Ann Arbor, MI 48109., Sherman SL; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322., Warren ST; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322.; Department of Biochemistry, School of Medicine, Emory University, Atlanta, GA 30322.; Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322., Jin P; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA 30322.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 May 31; Vol. 119 (22), pp. e2118124119. Date of Electronic Publication: 2022 May 26.
DOI:	10.1073/pnas.2118124119
Abstrakt:	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.
Databáze:	MEDLINE
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