Apoptotic phenotype induced by overexpression of wild-type gas3/PMP22: its relation to the demyelinating peripheral neuropathy CMT1A.
Although the Gas3/PMP22 protein is expressed at highest levels in differentiated Schwann cells, its presence, albeit at lower levels, in non-neuronal tissues and in NIH-3T3 growth-arrested fibroblasts argues for a more general function of this protein that is uncoupled to myelin structure. We show that gas3/PMP22 overexpression in NIH-3T3 growing cells leads to an apoptotic-like phenotype, which is suppressed by antioxidants and characterized by typical membrane blebbing, rounding up, and chromatin condensation, but with no evidence of DNA fragmentation. REF-52 fibroblasts seem to be completely refractive to gas3/PMP22 overexpression. Recently, several point mutations of the human gas3/PMP22 gene have been associated with Charcot-Marie-Tooth type 1A (CMT1A), a common hereditary demyelinating neuropathy. When gas3/PMP22 point mutations (L16P, S79C, T118M, and G150D) are similarly overexpressed in NIH-3T3 cells, the induced apoptotic-like phenotype as compared to the wild-type is significantly reduced. Both of the dominant mutations (L16P, S79C) for CMT1A behave as dominant negatives with respect to the wild type, whereas T118M, the only recessive mutant described, behaves as recessive under the same coexpression experiments. These data suggest a role for altered Schwann cell apoptosis in the pathogenesis of CMT1A.
Fabbretti
E
E
Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, Trieste, Italy.
Edomi
P
P
Brancolini
C
C
Schneider
C
C
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D002467:Cell Nucleus / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000209:etiology*; D003711:Demyelinating Diseases / Q000145:classification / Q000209:etiology*; D004926:Escherichia coli / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008845:Microinjections; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000096:biosynthesis* / Q000235:genetics; D017933:Peripheral Nervous System / Q000473:pathology*; D010641:Phenotype; D017354:Point Mutation; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D014018:Tissue Distribution
D009185:Myelin Proteins; C073687:PMP22 protein, human; C489545:Pmp22 protein, mouse; C489546:Pmp22 protein, rat; D011994:Recombinant Proteins