In vertebrates, including humans, rapid neuronal communication in the peripheral (PNS) and central nervous system (CNS) is dependent on proper myelination. The myelin-forming cell in the PNS is the Schwann cell (SC) and in the CNS the oligodendrocyte (OL). These specialized cells ensheath neuronal processes and thereby facilitate rapid propagation of electrical impulses. PNS myelin is defective in several types of Charcot-Marie-Tooth (CMT) disease, one of the most common inherited neurological disorders. Abnormal development of myelin in the CNS results in disorders known as leukodystrophies. We previously described the severe peripheral neuropathy CMT4J, caused by mutation of the human FIG4/SAC3 gene encoding an evolutionarily conserved lipid phosphatase that regulates intracellular vesicle trafficking along the endo-lysosomal pathway. The main objectives of our research are to understand the molecular mechanisms by which FIG4 deficiency disrupts myelin formation, and to develop treatment strategies for CMT4J in a preclinical model. Mutant mice with global loss of Fig4 expression (Fig4-/-) exhibit dramatic reduction of myelin in the CNS and PNS, severe tremor, and juvenile lethality. Electrophysiological recordings revealed slowed conduction of electrical impulses in sciatic and optic nerves. Surprisingly, the myelin defects in Fig4-/- mice can be """"""""rescued"""""""" by neuron-specific expression of wildtype Fig4. Based on these observations, we hypothesize that loss of Fig4 disrupts neuron-specific signaling mechanisms required for myelination.
In Specific Aim 1 and Aim 2 we use a combination of mouse genetics and proteomics to identify the neuronal myelination signals that are disrupted in Fig4 mutant mice and to determine the temporal requirement for Fig4 in vivo. These experiments will provide new mechanistic insights into the neuronal signals that direct myelinogenesis. To model human CMT4J, we developed transgenic mice that ubiquitously express low levels of the human disease allele Fig4-I41T on a Fig4-/- background (CMT4J mice). These mice exhibit hypomyelination comparable to that of Fig4-/- mice, but survive to adulthood with many neurologic features of the human disease. Since we have shown that transgenic expression of Fig4 in neurons is sufficient to drive myelination, we propose a gene therapy study in Specific Aim 3. Dorsal root ganglion neurons (PNS) and retinal ganglion cells (CNS) of CMT4J mice will be transduced with viral vectors to express wildtype Fig4. Myelination, nodal structure, and nerve conduction velocity in sciatic or optic nerve will be monitored as indicators of efficacy. Restoration of myelination by Fig4 gene therapy in mice would demonstrate a new therapeutic avenue for patients suffering from myelination disorders.
Malformation, degeneration or acute damage to myelin in the nervous system is observed in a broad spectrum of white matter disorders including leukodystrophies and multiple sclerosis in the central nervous system and Charcot-Marie-Tooth disease in the peripheral nervous system. The research described in this project uses a novel mouse genetic model to probe the molecular and biochemical processes involved in white matter disease. A better understanding of these processes will lay the foundation for the development of treatment strategies for nervous system white matter disorders.
|Shrager, Peter; Youngman, Margaret (2017) Preferential conduction block of myelinated axons by nitric oxide. J Neurosci Res 95:1402-1414|
|Mironova, Yevgeniya A; Lenk, Guy M; Lin, Jing-Ping et al. (2016) PI(3,5)P2 biosynthesis regulates oligodendrocyte differentiation by intrinsic and extrinsic mechanisms. Elife 5:|
|Wehner, Amanda B; Abdesselem, Houari; Dickendesher, Travis L et al. (2016) Semaphorin 3A is a retrograde cell death signal in developing sympathetic neurons. Development 143:1560-70|
|Lenk, Guy M; Frei, Christen M; Miller, Ashley C et al. (2016) Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene. Hum Mol Genet 25:340-7|
|Segal, Benjamin M; Giger, Roman J (2016) Stable biomarker for plastic microglia. Proc Natl Acad Sci U S A 113:3130-2|
|Baldwin, Katherine T; Carbajal, Kevin S; Segal, Benjamin M et al. (2015) Neuroinflammation triggered by ?-glucan/dectin-1 signaling enables CNS axon regeneration. Proc Natl Acad Sci U S A 112:2581-6|
|Carbajal, Kevin S; Mironova, Yevgeniya; Ulrich-Lewis, Justin T et al. (2015) Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. J Immunol 195:2552-9|
|Baldwin, Katherine T; Giger, Roman J (2015) Insights into the physiological role of CNS regeneration inhibitors. Front Mol Neurosci 8:23|
|Vaccari, Ilaria; Carbone, Antonietta; Previtali, Stefano Carlo et al. (2015) Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy. Hum Mol Genet 24:383-96|
|Duan, Yuntao; Wang, Shih-Hsiu; Song, Juan et al. (2014) Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells. Elife 3:|
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