CLC & MLC

Glial cells play a central role in brain fluid and ion homeostasis during neuronal activity. These functions are impaired in a leukodystrophy called MLC (megalencephalic leukoencephalopathy with subcortical cysts). Mutations in MLC1, the first gene defective to be discovered in MLC, impair surface expression and reduce the activity of volume-regulated chloride channels (VRAC). We have established a subset of biochemical and functional interactions among the ClC-2 chloride channel, GLIALCAM (a second gene defective in MLC) and MLC1, which likely represent components involved in the regulation of glial chloride fluxes. It has also been shown that mutations in CLCN2 underlie a specific form of human leukoencephalopathy. Using state-of-the-art biochemical and cellular assays, as well as novel knockout mouse and zebrafish models, we will understand the physiological role of the ClC-2 chloride channel in glial cells and we will decipher the relationships between the ClC-2 chloride channel and the MLC-defective proteins MLC1 and GlialCAM. We will identify the cellular quality control mechanisms that prematurely degrade MLC1 mutants. We plan to perform novel screens in order to identify pharmacological chaperones that restore the MLC1 mutant cell surface expression and could be used as therapies for MLC. This project will be instrumental to understand the pathophysiology of MLC disease and other brain defects in fluid homeostasis, hopefully providing the first therapeutic solutions for MLC patients.