Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16

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 Willis, Hai Yang Luo, Yu Sheng Li, Donte A. Stevens, Mi Bo Tang, Pan Du, Yao He Wang, Zheng Wei Hu & 2 others Yu Ming Xu, Jonathan C. Schisler

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere1007664
JournalPLoS Genetics
Volume14
Issue number9
DOIs
StatePublished - Sep 1 2018

Fingerprint

cognition
Cognition
mutation
Ligases
ligases
ubiquitin
Ubiquitin
Mutation
Cerebellar Diseases
Inborn Genetic Diseases
missense mutation
HSP70 Heat-Shock Proteins
Aptitude
proteasome endopeptidase complex
genetic disorders
Missense Mutation
Proteasome Endopeptidase Complex
protein
animal
Quality Control

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Shi, C. H., Rubel, C., Soss, S. E., Sanchez-Hodge, R., Zhang, S., Madrigal, S. C., ... Schisler, J. C. (2018). Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. PLoS Genetics, 14(9), [e1007664]. https://doi.org/10.1371/journal.pgen.1007664

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. / Shi, Chang He; Rubel, Carrie; Soss, Sarah E.; Sanchez-Hodge, Rebekah; Zhang, Shuo; Madrigal, Sabrina C.; Ravi, Saranya; McDonough, Holly; Page, Richard C.; Chazin, Walter J.; Patterson, Cam; Mao, Cheng Yuan; Willis, Monte; Luo, Hai Yang; Li, Yu Sheng; Stevens, Donte A.; Tang, Mi Bo; Du, Pan; Wang, Yao He; Hu, Zheng Wei; Xu, Yu Ming; Schisler, Jonathan C.

In: PLoS Genetics, Vol. 14, No. 9, e1007664, 01.09.2018.

Research output: Contribution to journalArticle

Shi, CH, Rubel, C, Soss, SE, Sanchez-Hodge, R, Zhang, S, Madrigal, SC, Ravi, S, McDonough, H, Page, RC, Chazin, WJ, Patterson, C, Mao, CY, Willis, M, Luo, HY, Li, YS, Stevens, DA, Tang, MB, Du, P, Wang, YH, Hu, ZW, Xu, YM & Schisler, JC 2018, 'Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16', PLoS Genetics, vol. 14, no. 9, e1007664. https://doi.org/10.1371/journal.pgen.1007664
Shi, Chang He ; Rubel, Carrie ; Soss, Sarah E. ; Sanchez-Hodge, Rebekah ; Zhang, Shuo ; Madrigal, Sabrina C. ; Ravi, Saranya ; McDonough, Holly ; Page, Richard C. ; Chazin, Walter J. ; Patterson, Cam ; Mao, Cheng Yuan ; Willis, Monte ; Luo, Hai Yang ; Li, Yu Sheng ; Stevens, Donte A. ; Tang, Mi Bo ; Du, Pan ; Wang, Yao He ; Hu, Zheng Wei ; Xu, Yu Ming ; Schisler, Jonathan C. / Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. In: PLoS Genetics. 2018 ; Vol. 14, No. 9.
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abstract = "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.",
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AU - Shi, Chang He

AU - Rubel, Carrie

AU - Soss, Sarah E.

AU - Sanchez-Hodge, Rebekah

AU - Zhang, Shuo

AU - Madrigal, Sabrina C.

AU - Ravi, Saranya

AU - McDonough, Holly

AU - Page, Richard C.

AU - Chazin, Walter J.

AU - Patterson, Cam

AU - Mao, Cheng Yuan

AU - Willis, Monte

AU - Luo, Hai Yang

AU - Li, Yu Sheng

AU - Stevens, Donte A.

AU - Tang, Mi Bo

AU - Du, Pan

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AU - Hu, Zheng Wei

AU - Xu, Yu Ming

AU - Schisler, Jonathan C.

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