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 diff erentiated Schwann cells, its presence, albeit at lower levels, in non -neuronal tissues and in NIH-3T3 growth-arrested fibroblasts argues fo r a more general function of this protein that is uncoupled to myelin structure. We show that gas3/PMP22 overexpression in NIH-3T3 growing c ells leads to an apoptotic-like phenotype, which is suppressed by anti oxidants 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 ove rexpression. 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 mut ations (L16P, S79C, T118M, and G150D) are similarly overexpressed in N IH-3T3 cells, the induced apoptotic-like phenotype as compared to the wild-type is significantly reduced. Both of the dominant mutations (L1 6P, S79C) for CMT1A behave as dominant negatives with respect to the w ild type, whereas T118M, the only recessive mutant described, behaves as recessive under the same coexpression experiments. These data sugge st a role for altered Schwann cell apoptosis in the pathogenesis of CM T1A.