ArticlePLoS genetics2018
Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 34 citations in OpenAlex.
- Domain-dependent uncoupling of the co-chaperone and E3 ubiquitin ligase CHIP underlies heterogeneity in spinocerebellar ataxia 48.The Journal of biological chemistry · 2026Article
- A protocol to establish and maintain organotypic cerebellar slice culture (OCerSC) from aged mice.PloS one · 2026Article
- Review
- E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.The EMBO journal · 2025Article
- Die Hard: Necroptosis and its Impact on Age-Dependent Neuroinflammatory Diseases.Frontiers in cell death · 2024Article
- Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination.Cell death & disease · 2023Article
- Review
- CHIP promotes the activation of NF-κB signaling through enhancing the K63-linked ubiquitination of TAK1.Cell death discovery · 2021Article
- Ubiquitin signaling in neurodegenerative diseases: an autophagy and proteasome perspective.Cell death and differentiation · 2021Review
- CHIP promotes Wnt signaling and regulates Arc stability by recruiting and polyubiquitinating LEF1 or Arc.Cell death discovery · 2021Article
- Chip Protein U-Box Domain Truncation Affects Purkinje Neuron Morphology and Leads to Behavioral Changes in Zebrafish.Frontiers in molecular neuroscience · 2021Article
- C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.Current neuropharmacology · 2021Review
- CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury.Nature communications · 2020Article
- CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons.Disease models & mechanisms · 2020Article
- CHIP as a therapeutic target for neurological diseases.Cell death & disease · 2020Review
- Clinical and pathologic phenotype of a large family with heterozygousNeurology. Genetics · 2020Article
- AAV/BBB-Mediated Gene Transfer of CHIP Attenuates Brain Injury Following Experimental Intracerebral Hemorrhage.Translational stroke research · 2020Article
- A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases.Frontiers in aging neuroscience · 2020Article
- Changes in protein function underlie the disease spectrum in patients with CHIP mutations.The Journal of biological chemistry · 2019Article
- Next Generation Precision Medicine: CRISPR-mediated Genome Editing for the Treatment of Neurodegenerative Disorders.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2019Review
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Authors and funding
22 authors at 6 institutions in 2 countries.
Funding
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.