ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
CHP1-mediated NHE1 biosynthetic maturation is required for Purkinje cell axon homeostasis.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 27 citations in OpenAlex.
- Targeting the Calcineurin Homologous Protein 1 (CHP1)-Transmembrane Protein 87A (TMEM87A) mechanosensing complex: a druggable vulnerability in metastatic ovarian cancer.Molecular biomedicine · 2026Article
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- Phenotypical, genotypical and pathological characterization of the moonwalker mouse, a model of ataxia.Neurobiology of disease · 2024Article
- Article
- Stress-induced reduction of NaScience advances · 2022Article
- Plastin 3 in health and disease: a matter of balance.Cellular and molecular life sciences : CMLS · 2021Review
- Structure and mechanism of the human NHE1-CHP1 complex.Nature communications · 2021Article
- The History of Gene Hunting in Hereditary Spinocerebellar Degeneration: Lessons From the Past and Future Perspectives.Frontiers in genetics · 2021Review
- Novel CHP1 mutation in autosomal-recessive cerebellar ataxia: autopsy features of two siblings.Acta neuropathologica communications · 2020Article
- The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force.Cerebellum (London, England) · 2019Review
- Sodium/Hydrogen Exchanger 1 Participates in Early Brain Injury after Subarachnoid Hemorrhage bothCell transplantation · 2019Article
- PLS3 Overexpression Delays Ataxia inFrontiers in neuroscience · 2019Article
- CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis.Brain : a journal of neurology · 2018Article
- Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function.Neurology. Genetics · 2018Article
- Long non-coding RNA deep sequencing reveals the role of macrophage in liver disorders.Oncotarget · 2017Article
- Mutations in the microtubule-associated protein 1A (Map1a) gene cause Purkinje cell degeneration.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Activation of AMP-activated protein kinase regulates hippocampal neuronal pH by recruiting Na(+)/H(+) exchanger NHE5 to the cell surface.The Journal of biological chemistry · 2014Article
- Article
- Endosomal pH in neuronal signaling and synaptic transmission: role of Na(+)/H(+) exchanger NHE5.Frontiers in physiology · 2014Review
- Endosomal acidification by Na+/H+ exchanger NHE5 regulates TrkA cell-surface targeting and NGF-induced PI3K signaling.Molecular biology of the cell · 2013Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Axon degeneration is a critical pathological feature of many neurodegenerative diseases. Misregulation of local axonal ion homeostasis has been recognized as an important yet understudied mechanism for axon degeneration. Here we report a chemically induced, recessive mouse mutation, vacillator (vac), which causes ataxia and concomitant axon degeneration of cerebellar Purkinje cells. By positional cloning, we identified vac as a point mutation in the calcineurin-like EF hand protein 1 (Chp1) gene that resulted in the production of mutant CHP1 isoforms with an amino acid substitution in a functional EF-hand domain or a truncation of this motif by aberrant splicing and significantly reduced protein levels. CHP1 has been previously shown to interact with the sodium hydrogen exchanger 1 (NHE1), a major regulator of intracellular pH. We demonstrated that CHP1 assists in the full glycosylation of NHE1 that is necessary for the membrane localization of this transporter and that truncated isoforms of CHP1 were defective in stimulating NHE1 biosynthetic maturation. Consistent with this, membrane localization of NHE1 at axon terminals was greatly reduced in Chp1-deficient Purkinje cells before axon degeneration. Furthermore, genetic ablation of Nhe1 also resulted in Purkinje cell axon degeneration, pinpointing the functional convergence of the two proteins. Our findings clearly demonstrate that the polarized presynaptic localization of NHE/CHP1 is an important feature of neuronal axons and that selective disruption of NHE1-mediated proton homeostasis in axons can lead to degeneration, suggesting that local regulation of pH is pivotal for axon survival.
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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.