| Peripheral myelin protein 22 (PMP22) is a hydrophobic, tetraspan protein of unknown function that is expressed mainly by myelinating Schwann cells (SC). Duplication, point mutations and deletion of PMP22 are associated with clinically related but different forms of demyelinating peripheral neuropathies of various degrees of severity. Since the neuropathies associated with the duplication and the point mutation paradigms are more severe than the one due to a lack of PMP22, a toxic gain of function of the mutated or excess of PMP22 has been proposed. However, the nature of this toxic gain of function remains elusive so far. To study this, we have used the Trembler J (TrJ) mouse model of peripheral neuropathy that carries a point mutation in PMP22. In sciatic nerves of the TrJ mouse, PMP22 has a reduced turnover rate when compared to the normal or the heterozygous deficient-protein. In TrJ nerves, PMP22 accumulates in cytoplasmic aggregates that recruit molecular chaperones as well as components of the ubiquitin-proteasomal and autophagic-lysosomal pathways. The presence of such aggregates in TrJ nerves correlates with reduced activity of the proteasomal pathway and accumulation of ubiquitinated substrates, including PMP22. Utilizing a pharmacological approach in cultured SC, we have shown that under permissive conditions, the aggregates are removed by an autophagic-dependent mechanism. In support of the involvement of autophagy in the TrJ nerves, autophagosomes are present in the SC cytoplasm and the localization and levels of autophagic components are altered. Furthermore, the formation of new aggresomes is hindered by enhancement of autophagy and molecular chaperones, suggesting that different cellular pathways cooperate to prevent the accumulation of misfolded/non-functional proteins in the cell. Based on these results, we propose that the formation of aggregates is a protective response of the SC by which the misfolded/unfunctional PMP22 is concentrated in a central location to be delivered by autophagy to lysosomes for degradation. However, with additional insults and aging, these degradation pathways become less efficient and aggregates could accumulate, which could contribute to SC dysfunction through sequestering essential SC components and affecting proteasome functioning. |
