There and Back Again: A Protein’s Tale Uncovering the Quality Control Factors Mediating Peripheral Myelin Protein 22 Trafficking

Abstract

Charcot-Marie Tooth disease (CMTD) is the most common inherited neuropathy of the peripheral nervous system (PNS) and afflicts roughly 1 in 2,500 individuals. Over 70% of patients afflicted with this disease have a mutation in the protein encoding pmp22 gene. PMP22 is a tetraspan integral membrane protein of unknown function that is highly expressed at the plasma membrane (PM) of myelinating Schwann cells of the PNS. Improper gene dosage of pmp22 in CMTD patients results in either too much or too little PMP22 at the PM of Schwann cells. The altered amount of PMP22 at the PM is believed to cause the myelin abnormalities observed in these patients. There are currently no treatments for CMTD. In this dissertation, I show that PMP22 is able to alter membrane ultrastructure in vitro uncovering a novel function of the protein. I also show that PMP22 has a distinct affinity for cholesterol-rich membrane domains and that this affinity is correlated with PM trafficking. Finally, I explored factors that mediated PMP22 trafficking efficiency. I showed that increased expression of PMP22 decreases trafficking efficiency, N-linked glycosylation limits PMP22 expression at the PM, and several endoplasmic reticulum resident chaperones interact with PMP22 impact its trafficking efficiency. The results from this work shed light on PMP22 folding and trafficking and could be used to uncover novel therapeutic approaches for the treatment of CMTD.