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Pathogenic P0 mutations are blocked at various quality control check points.
Author(s) -
Tinelli Elisa,
Modica Graziana,
Domenica Vizzuso,
Feltri Maria Laura,
Wrabetz Lawrence
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.850.9
Subject(s) - endoplasmic reticulum , er retention , golgi apparatus , mutant , microbiology and biotechnology , transmembrane protein , myelin , serine , glycoprotein , extracellular , intracellular , point mutation , chemistry , biology , biochemistry , gene , central nervous system , neuroscience , receptor , phosphorylation
In peripheral nerve, Schwann cells enwrap axons and form myelin. P0 is the most abundant transmembrane glycoprotein produced by Schwann cells, where it is normally delivered to the myelin sheath. Alterations of the dosage or the sequence of P0 cause diverse peripheral neuropathies, like Charcot Marie Tooth (CMT) or Dejerine Sottas Syndrome (DSS). Deletion of serine 63 (S63del), the first amino acid (aa) of the β‐strand C of the extracellular domain, causes the retention of the protein in the endoplasmic reticulum (ER)‐Golgi complex. Protein quality control in the ER ensures that only correctly synthesized proteins are delivered to the final destination. Here we correlate mutations in aa important for the maturation of P0, with their neuropathy phenotypes. Alteration of the glycosylation site does not alter the trafficking, whereas mutation of aa important for the formation of the disulfide bond cause retention of the mutant proteins in the ER‐Golgi compartment. Interestingly, the retention of mutants in the β‐strand C or in the cysteines of the disulfide bond is mediated by two different sets of chaperones, suggesting multiple check points mediate P0 maturation. Therefore, some P0 mutants exit the quality control and are pathogenic in the myelin sheath, whereas others are retained at various points of maturation in the ER. However, the location of intracellular P0 retention does not define the neuropathy phenotype.