OVERLOADED ENDOPLASMIC RETICULUM-GOLGI COMPARTMENTS, A POSSIBLE PATHOMECHANISM OF PERIPHERAL NEUROPATHIES CAUSED BY MUTATIONS OF THE PERIPHERAL MYELIN PROTEIN PMP22

Nonconservative point mutations of the peripheral myelin protein 22 (P MP22) are associated with Charcot-Marie-Tooth type 1A disease, the mos t common inherited peripheral neuropathy in humans, and with the Tremb ler J (TrJ) and Trembler (Tr) alleles in mice. We investigated the int racellular transport of wild-type PMP22 and its TrJ and Tr mutant form s in Schwann cells and in a non-neuronal cell line. In contrast to wil d type, mutant proteins were not inserted into the plasma membrane and accumulated in the endoplasmic reticulum and Golgi compartments. Coex pression of each mutant with wild-type PMP22 confirmed the different i ntracellular distribution of the mutant forms, indieating that neither the TrJ nor Tr protein has a dominant-negative effect on the cellular distribution of wild-type PMP22. Accumulation of PMP22 immunoreactivi ty in the cell body of myelinating Schwann cells was also observed in nerve biopsies obtained from CMT1A patients carrying the TrJ point mut ation. We propose that impaired trafficking of mutated PMP22 affects S chwann cell physiology leading to myelin instability and loss.