Roles of Myotubularin PI 3-phosphatases in Demyelinating Peripheral Neuropathy

Oregon Health & Science University, Portland OR

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Abstract

This is an application for activation of the ROO phase of tljie K99/R00 grant 5K99NS057903-02. The Candidate. Dr. Fred Robinson, has nearly completed twd years of mentored training in the Laboratory of Dr. Jack Dixon at the University of California San Diego. The Candidate proposes to carry out the independent (ROO) phase of the award at Oregon Health &Science University in the Department of Neurology and Jungers Center for Neurosciences Research. The long term career goal of the Candidate is to become an independent investigator who contributes significantly to the peripheral neuropathy field, and. more generaly, to our understanding of the functions of phosphoinositides in the nervous system. The overall goal ofthe proposed work is to understand how mutations in myotubularin family phosphoinositide (PI) 3-phosphatases lead to Charcot-Marie-Tooth (CMT) peripheral neuropathy. Type 4B CMT (CMT4B) is a severe form of the disease in which the myelin sheaths of nerves are abnormal. Mutations in the genes for either myotubularin related protein 2 (MTMR2) or MTMR13 cause CMT4B. The Candidate has demonstrated that the MTMR2 and MTMR13 PI 3-phosphatases fomn a membraneassociated complex capable of regulating 3-phosphoinosttides. As loss of either MTMR2 or MTMR13 is sufficient to cause CMT4B, MTMR13 is likely an essential regulator of MTMR2. To further probe the relationship between MTMR2 and MTMR13. the Candidate has generated Mtmr13-deficient mice. The specific aims of the proposal are: (1) Validate Mtmrl 3-deficient mice as a model of CMT4B2 disease, using electrophysiology, histology and electron microscopy. (2j Examine the impact of loss of Mtmrl 3 on Mtmr2 function, using biochemical and cel! biological methods. (3) Determine how 3-phosphoinositide homeostasis and endosomal-lysosomal trafficking are perturbed in Mtrhrl 3-deficient Schwann cells, using cell biological analyses. Understanding how the Schwann cell endosomal-lysosomal pathway is altered by the dysregulation of 3-phosphoinositides may allow us to consider pharmacological modulation of the pathway as a therapeutic strategy.