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

التفاصيل البيبلوغرافية
العنوان: Identification of PSMB5 as a genetic modifier of fragile X-associated tremor/ataxia syndrome.
المؤلفون: 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.
المصدر: 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.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : National Academy of Sciences
مواضيع طبية MeSH: Ataxia*/genetics , Fragile X Syndrome*/genetics , Proteasome Endopeptidase Complex*/genetics , Tremor*/genetics, Animals ; Disease Models, Animal ; Drosophila melanogaster ; Fragile X Mental Retardation Protein/genetics ; Humans ; Male
مستخلص: 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.
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معلومات مُعتمدة: R01 NS086810 United States NS NINDS NIH HHS; U54 NS091859 United States NS NINDS NIH HHS; I01 BX004842 United States BX BLRD VA; UL1 TR000424 United States TR NCATS NIH HHS; R01 NS099280 United States NS NINDS NIH HHS; R01 AG056533 United States AG NIA NIH HHS; P50 HD103573 United States HD NICHD NIH HHS; R56 AG062633 United States AG NIA NIH HHS; P50 HD104463 United States HD NICHD NIH HHS; R35 NS111602 United States NS NINDS NIH HHS; R01 NS051630 United States NS NINDS NIH HHS
فهرسة مساهمة: Keywords: FMR1; FXTAS; PSMB5; fragile X syndrome; premutation
المشرفين على المادة: 0 (FMR1 protein, human)
139135-51-6 (Fragile X Mental Retardation Protein)
EC 3.4.25.1 (PSMB5 protein, human)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SCR Disease Name: Fragile X Tremor Ataxia Syndrome
تواريخ الأحداث: Date Created: 20220526 Date Completed: 20220530 Latest Revision: 20231019
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC9295734
DOI: 10.1073/pnas.2118124119
PMID: 35617426
قاعدة البيانات: MEDLINE
الوصف
تدمد:1091-6490
DOI:10.1073/pnas.2118124119