PMP22 is primarily expressed in myelinating Schwann cells. PMP22 is the culprit gene responsible for the most highly prevalent forms of Charcot-Marie-Tooth disease (CMT) with over-expression of PMP22 causing CMT1A, deletion of PMP22 causing hereditary neuropathy with liability to pressure palsies (HNPP) and Trembler-J (TrJ) point mutation causing CMT1E. These diseases suggest that PMP22 level has to be tightly controlled to maintain the wellbeing of the peripheral nerve. We have identified a novel myelin protein, Small Valosin Interacting Protein (SVIP). SVIP interacts with Valosin-Containing Protein (VCP;also called p97), a highly conserved ATPase that is ubiquitously distributed. VCP forms a hexameric functional unit that plays important roles in a variety of cellular functions, including endoplasmic reticulum-associated degradation (ERAD) and autophagy. These highly diversified functions are achieved through VCP interactions with over 27 different cofactors. SVIP is one of them. Our preliminary data show that SVIP is highly expressed in myelinating glia and neurons but is minimal or absent in other tissues. SVIP appears to be important in proteasomal/autophagic degradation. Moreover, our preliminary study has shown that the toxic gain-of-function mutation in Pmp22 drastically suppresses the expression of SVIP in Schwann cells, which would block autophagy and impair the protein degradation. This finding is highly relevant to the pathogenesis in the PMP22-related diseases. Toward this end, we propose the following specific aims:
Aim 1. To determine whether null function of SVIP in vivo is sufficient to cause abnormal protein aggregation in myelin. This will be tested using constitutive and conditional knockout mice of Svip.
Aim 2. To test the hypothesis that mutant PMP22 promotes protein aggregation by suppressing SVIP expression that would normally activate autophagy processes in Schwann cells. In this aim, we will knockout Svip or over-express Svip to determine how SVIP affects PMP22 degradation in the mutant Schwann cells. Taken together, this study is expected to yield a series of important findings that do not exist in the current literatures. First, it will deepen our understanding how SVIP regulates protein degradation in myelin in vivo by investigating Svip knockout and Pmp22 transgenic mice. Second, results should establish a pathogenic signaling pathway responsible for abnormal protein aggregation in mutant Schwann cells. Finally, knowledge derived from this study should have broad implications in other neurodegenerative disorders with abnormal protein aggregates.
PMP22-related neuropathies, including CMT1A, are the most common forms of inherited peripheral nerve diseases. Our recent studies have identified a novel signaling pathway that is essential in the protein degradation of PMP22. This project will use several mouse models to investigate how this signaling pathway regulates PMP22 degradation, which may yield new therapeutic targets for CMT1A.
