Robinson Lab
Phosphoinositide signaling, axonal degeneration and neurological disease
| Recent Publications Personnel |
The overall goal of our research is to determine how disturbances in phosphoinositide signaling lead to cellular dysfunction and human disease. Mutations in phosphoinositide (PI) phosphatases cause a number of human neurological diseases, including conditions affecting the central and peripheral nervous systems. For example, mutations in several members of the myotubularin family of PI 3-phosphatases lead to Charcot-Marie-Tooth (CMT) peripheral neuropathy, one of most common inherited neurological disorders, which affects about 1 in 2500 worldwide. CMT causes progressive degeneration of muscles in the extremities as well as loss of sensory function.
Figure 1
Inositol lipids, a component of cell membranes, are at the crossroads of critical membrane-based cell signaling events. In eukaryotic cells, including neurons and glia, phosphatidylinositol (PtdIns) can be phosphorylated on the D3, D4 and D5 positions of the inositol ring, leading to the formation of seven distinct phosphatidylinositol polyphosphates, usually called phosphoinositides (PIs). As membrane-tethered signaling molecules, PIs regulate membrane trafficking, cell growth and survival, cell division and cellular motility. PIs also play key roles in the regulation of ion channels, often acting as direct activators.
Figure 2
We are investigating how mutations in members of the myotubularin family of PI 3-phosphatases disrupt PI signaling, and thus cause alterations in endosomal-lysosomal membrane trafficking that lead to peripheral neuropathy. In addition, we are investigating the functions of phosphoinositide signaling in the central nervous system. Myotubularin PI 3-phosphatases specifically dephosphorylate PtdIns3P and PtdIns(3,5)P2, two PIs that regulate membrane traffic within the endosomal-lysosomal pathway. Mutations in the genes for either myotubularin related protein 2 (MTMR2) or MTMR13 cause type 4B CMT (CMT4B), a severe form of the disease characterized by abnormal myelin sheaths and secondary axonal degeneration. We demonstrated that the MTMR2 and MTMR13 phosphatases form a membrane-associated complex that is capable of regulating 3-phosphoinositides (Figure 1). Notably, the MTMR13 protein lacks phosphatase activity. As loss of either MTMR2 or MTMR13 is sufficient to cause CMT4B, MTMR13 is likely an essential, non-catalytic regulator of MTMR2. To further probe the relationship between MTMR2 and MTMR13, we recently generated Mtmr13-deficient mice, thus establishing a valuable mouse model of human CMT4B2 disease (Figure 2).
Our work will provide novel insights into how dysregulation of PtdIns3P and PtdIns(3,5)P2 leads to cellular dysfunction and neurological disease. This work also has the potential to lead to therapies for peripheral neuropathies and other diseases of myelin. Understanding how the Schwann cell endosomal-lysosomal pathway is altered by the dysregulation of 3-phosphoinositides is critical to the design of an appropriate pharmacological intervention in CMT4B. In addition, the identification of downstream targets of Mtmr2-Mtmr13 may allow us to define novel signaling pathways, both in the peripheral and central nervous system.
Recent publications
Robinson, F. L., Niesman, I. R., Beiswenger, K. and Dixon, J. E. (2008). Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice. Proc Natl Acad Sci U S A. 105:4916-4921.
Robinson, F. L. and Dixon, J. E. (2006). Myotubularin phosphatases: Policing 3-phosphoinositides. Trends Cell Biol. 16:403-412.
Robinson, F. L. and Dixon, J. E. (2005). The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-Tooth disease. J. Biol. Chem. 2005:31699-31707.
Personnel
Fred L. Robinson
Ph.D., University of Texas Southwestern, 2002
Postdoctoral Fellow, University of California at San Diego, 2002-2009
Dr. Robinson joined the Jungers Center as an Assistant Scientist and Assistant Professor of Neurology in August 2009. Dr. Robinson received an undergraduate degree at Oregon State University in biology and genetics, and a master’s degree in biological sciences from the University of Nebraska-Lincoln. After graduate training in Biochemistry at UT Southwestern with Melanie Cobb, he joined the laboratory of Jack Dixon at the University of California, San Diego in 2002. Dr. Robinson is a recipient of a prestigious NIH Pathway to Independence Award, which will facilitate the development of his laboratory in the Jungers Center.
Priya Bhatt
BS, University of Washington, 2009
I am currently a research assistant in the lab. My true passion for research began in high school where I paired up with a lab at OHSU to study the role of NOD2 gene expression in acute anterior uveitis. At the University of Washington, I continued my molecular research endeavors by studying the influenza virus. In my free time, I enjoy participating in East Indian cultural dance.
In the Robinson lab, I am studying how membrane traffic is disrupted in a mouse model of demyelinating peripheral neuropathy. I use immunofluorescence microscopy and biochemical techniques to address this scientific question, in hopes of finding clues that will lead to treatments for this debilitating condition.
Eric Schmidt
BS, University of Kansas, 2008
After graduating with a degree in genetics, I worked for a year at the University of Kansas on a large quantitative genetics project. The project was to create a community resource of Drosophila lines for use in QTL mapping including minor alleles and to use this resource to identify loci related to traits such as nicotine tolerance. I recently moved to Oregon and am taking the opportunity to explore another area of research in the field of biology. In the Robinson lab, I am investigating the biochemical functions of the enigmatic MTMR13 protein, which is mutated in Charcot-Marie-Tooth disease type 4B.
