Yan Hua Lee1,2, Yu-Shuen Tsai3, Che-Chang Chang4, Chun-Chen Ho2, Hsiu-Ming Shih2, Hui-Mei Chen2, Hsing-Lin Lai2, Chia-Wei Lee2, Yi-Chung Lee5, Yi-Chu Liao5, Ueng-Cheng Yang3,6, Tzu-Hao Cheng1,7, Yijuang Chern1,2, Bing-Wen Soong5,8. 1. Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan. 2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. 3. Center for Systems and Synthetic Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan. 4. The Ph.D. Program for Translational Medicine and International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. 5. Department of Neurology, Taipei Veterans General Hospital, and Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan. 6. Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan. 7. Institute of Biochemistry and Molecular Biology, and Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan. 8. Department of Neurology, Shuang Ho Hospital, and Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan.
Abstract
BACKGROUND: Polyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an expansion of the polyQ-encoding CAG repeats in the disease-causing gene. The length of the CAG repeats is the major determiner of the age at onset (AO) of polyQ diseases, including Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3). OBJECTIVE: We set out to identify common genetic variant(s) that may affect the AO of polyQ diseases. METHODS: Three hundred thirty-seven patients with HD or SCA3 were enrolled for targeted sequencing of 583 genes implicated in proteinopathies. In total, 16 genes were identified as containing variants that are associated with late AO of polyQ diseases. For validation, we further investigate the variants of PIAS1 because PIAS1 is an E3 SUMO (small ubiquitin-like modifier) ligase for huntingtin (HTT), the protein linked to HD. RESULTS: Biochemical analyses revealed that the ability of PIAS1S510G to interact with mutant huntingtin (mHTT) was less than that of PIAS1WT , resulting in lower SUMOylation of mHTT and lower accumulation of insoluble mHTT. Genetic knock-in of PIAS1S510G in a HD mouse model (R6/2) ameliorated several HD-like deficits (including shortened life spans, poor grip strength and motor coordination) and reduced neuronal accumulation of mHTT. CONCLUSIONS: Our findings suggest that PIAS1 is a genetic modifier of polyQ diseases. The naturally occurring variant, PIAS1S510G , is associated with late AO in polyQ disease patients and milder disease severity in HD mice. Our study highlights the possibility of targeting PIAS1 or pathways governing protein homeostasis as a disease-modifying approach for treating patients with HD.
BACKGROUND: Polyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an expansion of the polyQ-encoding CAG repeats in the disease-causing gene. The length of the CAG repeats is the major determiner of the age at onset (AO) of polyQ diseases, including Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3). OBJECTIVE: We set out to identify common genetic variant(s) that may affect the AO of polyQ diseases. METHODS: Three hundred thirty-seven patients with HD or SCA3 were enrolled for targeted sequencing of 583 genes implicated in proteinopathies. In total, 16 genes were identified as containing variants that are associated with late AO of polyQ diseases. For validation, we further investigate the variants of PIAS1 because PIAS1 is an E3 SUMO (small ubiquitin-like modifier) ligase for huntingtin (HTT), the protein linked to HD. RESULTS: Biochemical analyses revealed that the ability of PIAS1S510G to interact with mutant huntingtin (mHTT) was less than that of PIAS1WT , resulting in lower SUMOylation of mHTT and lower accumulation of insoluble mHTT. Genetic knock-in of PIAS1S510G in a HD mouse model (R6/2) ameliorated several HD-like deficits (including shortened life spans, poor grip strength and motor coordination) and reduced neuronal accumulation of mHTT. CONCLUSIONS: Our findings suggest that PIAS1 is a genetic modifier of polyQ diseases. The naturally occurring variant, PIAS1S510G , is associated with late AO in polyQ disease patients and milder disease severity in HD mice. Our study highlights the possibility of targeting PIAS1 or pathways governing protein homeostasis as a disease-modifying approach for treating patients with HD.