Document Type


Degree Name



Oregon Health & Science University


The myotubularin (MTMR) family of phosphoinositide (PI) 3-phosphatases specifically catalyze the dephosphorylation of phosphatidylinositol 3-phosphate (PI3P) and 3,5-disphosphate (PI(3,5)P2), two lipids that regulate membrane traffic within the endosomal-lysosomal pathway. A number of studies have shown that phosphoinositide regulation in endosomal-lysosomal pathways is critical for functional myelination. This is highlighted by seven disease-causing mutations in human endosomal-related genes (FIG4, MTMR2, MTMR5, MTMR13, FRABIN/FGD4, SH3TC2 and SIMPLE/LITAF) that cause demyelinating forms of Charcot-Marie-Tooth (CMT) peripheral neuropathy. In humans, loss of MTMR2, MTMR5, or MTMR13 causes CMT type 4B1, 2, or 3, respectively. CMT peripheral neuropathies are challenging to treat clinically because the molecular pathogenesis behind known inherited gene mutations remains unclear. By studying demyelinating CMT genes and their function in Schwann cells, we hope to elucidate the molecular mechanisms that lead to demyelination and secondary axonal degeneration. To do this, we use a CMT4B mouse model (Mtmr13-/-) to investigate resulting changes in cellular signaling pathways, endo-lysosomal membranes, and PI levels that might contribute to myelin dysregulation. The research performed in this dissertation further characterizes our CMT4B mouse model and describes the localization of endogenous mouse Mtmr2 and Mtmr13 proteins in Schwann cells. We also use this mouse model to attempt to rescue Mtmr13-/--related myelin outfoldings by PI 3-kinase knockouts. We take a novel approach to studying PIs in Schwann cells by exploring the role PI 3-kinases play in myelination, something that had never been done previously. Together, the data presented here advances the understanding of the molecular and PI changes that result from MTMR13 mutations and how these changes contribute to disease pathogenesis and progression.




Neuroscience Graduate Program


School of Medicine

Included in

Neurosciences Commons



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