ArticleThe Journal of biological chemistry2018
Most mutations that cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16) destabilize the protein quality-control E3 ligase CHIP.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- 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 novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.BMC neurology · 2026Article
- Protein degradation kinetics measured by microinjection and live-cell fluorescence microscopy.Scientific reports · 2024Article
- Chaperone-assisted E3 ligase CHIP: A double agent in cancer.Genes & diseases · 2022Review
- TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment.Cellular and molecular neurobiology · 2022Review
- The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP.The Journal of biological chemistry · 2022Article
- Chemical Regulation of the Protein Quality Control E3 Ubiquitin Ligase C-Terminus of Hsc70 Interacting Protein (CHIP).Chembiochem : a European journal of chemical biology · 2022Article
- The UBE2D ubiquitin conjugating enzymes: Potential regulatory hubs in development, disease and evolution.Frontiers in cell and developmental biology · 2022Review
- Genetic Dominant Variants inInternational journal of molecular sciences · 2021Article
- Functional analysis of tomato CHIP ubiquitin E3 ligase in heat tolerance.Scientific reports · 2021Article
- C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.Current neuropharmacology · 2021Review
- 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
- Spinocerebellar ataxia type 48: last but not least.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2020Review
- UbcH5 Interacts with Substrates to Participate in Lysine Selection with the E3 Ubiquitin Ligase CHIP.Biochemistry · 2020Article
- Clinical and pathologic phenotype of a large family with heterozygousNeurology. Genetics · 2020Article
- HeterozygousNeurology. Genetics · 2020Article
- The E3 ubiquitin ligase CHIP in normal cell function and in disease conditions.Annals of the New York Academy of Sciences · 2020Review
- Guilt-by-Association - Functional Insights Gained From Studying the LRRK2 Interactome.Frontiers in neuroscience · 2020Review
- A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases.Frontiers in aging neuroscience · 2020Article
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3 authors.
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Abstract
The accumulation of misfolded proteins promotes protein aggregation and neuronal death in many neurodegenerative diseases. To counteract misfolded protein accumulation, neurons have pathways that recognize and refold or degrade aggregation-prone proteins. One U-box-containing E3 ligase, C terminus of Hsc70-interacting protein (CHIP), plays a key role in this process, targeting misfolded proteins for proteasomal degradation. CHIP plays a protective role in mouse models of neurodegenerative disease, and in humans, mutations in CHIP cause spinocerebellar ataxia autosomal recessive type 16 (SCAR16), a fatal neurodegenerative disease characterized by truncal and limb ataxia that results in gait instability. Here, we systematically analyzed CHIP mutations that cause SCAR16 and found that most SCAR16 mutations destabilize CHIP. This destabilization caused mutation-specific defects in CHIP activity, including increased formation of soluble oligomers, decreased interactions with chaperones, diminished substrate ubiquitination, and reduced steady-state levels in cells. Consistent with decreased CHIP stability promoting its dysfunction in SCAR16, most mutant proteins recovered activity when the assays were performed below the mutants' melting temperature. Together, our results have uncovered the molecular basis of genetic defects in CHIP function that cause SCAR16. Our insights suggest that compounds that improve the thermostability of genetic CHIP variants may be beneficial for treating patients with SCAR16.
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