Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar a...
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Public Library of Science (PLoS)
2018-09-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1007664 |
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| author | Chang-He Shi Carrie Rubel Sarah E Soss Rebekah Sanchez-Hodge Shuo Zhang Sabrina C Madrigal Saranya Ravi Holly McDonough Richard C Page Walter J Chazin Cam Patterson Cheng-Yuan Mao Monte S Willis Hai-Yang Luo Yu-Sheng Li Donte A Stevens Mi-Bo Tang Pan Du Yao-He Wang Zheng-Wei Hu Yu-Ming Xu Jonathan C Schisler |
| author_facet | Chang-He Shi Carrie Rubel Sarah E Soss Rebekah Sanchez-Hodge Shuo Zhang Sabrina C Madrigal Saranya Ravi Holly McDonough Richard C Page Walter J Chazin Cam Patterson Cheng-Yuan Mao Monte S Willis Hai-Yang Luo Yu-Sheng Li Donte A Stevens Mi-Bo Tang Pan Du Yao-He Wang Zheng-Wei Hu Yu-Ming Xu Jonathan C Schisler |
| author_sort | Chang-He Shi |
| collection | DOAJ |
| description | CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease. |
| format | Article |
| id | doaj-art-65933774acf445dba5e78330c3afc93f |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2018-09-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj-art-65933774acf445dba5e78330c3afc93f2025-08-20T03:09:35ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042018-09-01149e100766410.1371/journal.pgen.1007664Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.Chang-He ShiCarrie RubelSarah E SossRebekah Sanchez-HodgeShuo ZhangSabrina C MadrigalSaranya RaviHolly McDonoughRichard C PageWalter J ChazinCam PattersonCheng-Yuan MaoMonte S WillisHai-Yang LuoYu-Sheng LiDonte A StevensMi-Bo TangPan DuYao-He WangZheng-Wei HuYu-Ming XuJonathan C SchislerCHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.https://doi.org/10.1371/journal.pgen.1007664 |
| spellingShingle | Chang-He Shi Carrie Rubel Sarah E Soss Rebekah Sanchez-Hodge Shuo Zhang Sabrina C Madrigal Saranya Ravi Holly McDonough Richard C Page Walter J Chazin Cam Patterson Cheng-Yuan Mao Monte S Willis Hai-Yang Luo Yu-Sheng Li Donte A Stevens Mi-Bo Tang Pan Du Yao-He Wang Zheng-Wei Hu Yu-Ming Xu Jonathan C Schisler Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. PLoS Genetics |
| title | Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. |
| title_full | Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. |
| title_fullStr | Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. |
| title_full_unstemmed | Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. |
| title_short | Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. |
| title_sort | disrupted structure and aberrant function of chip mediates the loss of motor and cognitive function in preclinical models of scar16 |
| url | https://doi.org/10.1371/journal.pgen.1007664 |
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