CHP1-mediated NHE1 biosynthetic maturation is required for Purkinje cell axon homeostasis.
Document Type
Article
Publication Date
7-31-2013
Keywords
Age Factors, Alkylating Agents, Animals, Ataxia, Axons, Calcium-Binding Proteins, Cation Transport Proteins, Cells, Cultured, Cerebellum, Cricetinae, Disease Models, Animal, Ethylnitrosourea, Female, Gene Expression Regulation, Developmental, Homeostasis, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Nerve Tissue Proteins, Point Mutation, Purkinje Cells, Sodium-Hydrogen Antiporter
JAX Source
J Neurosci. 2013 Jul 31;33(31):12656-69.
Volume
33
Issue
31
First Page
12656
Last Page
12669
ISSN
1529-2401
PMID
23904602
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. J Neurosci. 2013 Jul 31;33(31):12656-69.
Recommended Citation
Liu Y,
Zaun H,
Orlowski J,
Ackerman SL.
CHP1-mediated NHE1 biosynthetic maturation is required for Purkinje cell axon homeostasis. J Neurosci. 2013 Jul 31;33(31):12656-69.