The overarching theme of the work in my laboratory is the roles of connexins in the function of central nervous system (CNS) and peripheral nervous system (PNS) glia. Charcot-Marie-Tooth disease is a group of inherited disorders that predominantly or exclusively affect the PNS. CMT1X, the X-linked form of Charcot-Marie-Tooth disease, is associated with mutations in connexin 32 (Cx32), a gap junction protein expressed in Schwann cells (SCs) and in oligodendrocytes in the CNS. One focus of my lab is elucidating the mechanisms by which CMTX mutations lead to peripheral neuropathy. We have previously shown that form the standpoint of RNA expression, the peripheral nerves of mice lacking Cx32 show a remarkable resemblance to injured nerves from wild-type mice. However, axon loss is the cause of disability in this and other related diseases. Thus, we have been working to identify the changes occurring at the axonal level. We have recently used proteomic approaches to show that a number of RNA trafficking proteins are dysregulated in the motor neurons of several animal models of CMT1X, suggesting that altered RNA trafficking may underlie the axonal loss seen in CMT1X.
Rotation projects may include experiments to identify the specific RNAs being affected by these alterations in RNA trafficking, which should give us further insight into the pathogenesis of CMT1X, as well as spatial metabolomic and protein expression studies to identify metabolic and protein expression changes within the axons themselves. In addition, we have identified a number of signaling pathways between Schwann cell and axon that may be contributing to axonal degeneration; these also need to be further investigated. Rotating students will also have the opportunity to gain experience with bioinformatic techniques for the analysis of the proteomic and transcriptomic data sets by interacting with our bioinformatic collaborators.
Mutations in human Cx47 cause either a mild disorder, (hereditary spastic paraparesis HSP) or a more severe leukodystrophy (Pelizaeus-Merzbacher like disease, PMLD) Rotating students may choose to be involved in a project using patch clamping and standard cell biological techniques (see attached article) as well as molecular modeling of our findings in silico to evaluate functional properties of mutant forms of Cx47 in an effort to understand both how specific changes in primary protein structure affect the function of Cx47 and to elucidate the reasons patients harboring mutations in Cx47 develop mild or severe diseases.
– Investigating Oligodendrocyte Connexins
– Gene expression profiling studies in regenerating nerves in a mouse model for CMT1X: Uninjured Cx32-knockout peripheral nerves display expression profile of injured wild type nerves.
– Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations.