Myelination is required for normal axonal maturation, and axon survival depends upon oligodendrocyte and Schwann cell support after myelination. Late onset axonopathies and axonal degeneration develop in mice null for PLP and in mice where PLP was replaced by P0 protein. While alterations of axonal cytoskeleton and axonal transport precede axonal degeneration in these mice, little is known about the molecular mechanisms responsible for myelin-induced axonal pathology. The goal of this proposal is to determine how myelin modulates axonal function and survival. Our studies are based upon the hypothesis that myelin regulates post translational modifications of axonal proteins that maintain microtubule stability and mitochondrial fusion/fission.
Specific Aim 1 is focused on the role of the most abundant myelin proteins, P0 and PLP, by investigating the effects of replacing P0 with PLP in myelinating Schwann cells. We specifically ask if PLP can replace P0 as the structural protein of compact PNS myelin, and if this has a detrimental effect on the function or survival of axons.
Specific Aim 2 is focused on the role of PLP in maintaining CNS axonal integrity by investigating axonal cytoskeletal changes that precede axonal degeneration in P0-CNS mice. Based on our preliminary findings of altered microtubule length, orientation and stability, these studies are designed to 1) identify upstream myelin-axon signaling events that maintain the axonal cytoskeleton and 2) provide direction for the development of axon-protective therapies by modulation of kinases and phosphatases.
Specific Aim 3 will investigate how myelin regulates axonal mitochondrial distribution and transport. Mitochondria are essential to normal axonal function and are the major source of the ATP needed for saltatory conduction and axonal transport. Reduced energy production is considered a major cause of axonal degeneration in diseases of myelin. Axons contain both stationary and motile mitochondrial pools. We will investigate the effects of myelination, demyelination and dysmyelination on mitochondrial transport, mitochondrial stationary site distribution and mitochondrial fusion/fission in wild type and P0-CNS mice. Preliminary data support the feasibility of these studies, which should provide the first description of the effects of myelin on mitochondrial distribution and transport. This knowledge is essential for future therapeutics that will target axonal energy production in diseases of myelin.
This project will continue to develop our knowledge of the role of myelin in neurological development and in neurodegenerative diseases. The results will contribute to understanding myelin disease pathology and provide clues for effective future therapeutic strategies for treating primary myelin diseases.
|Yin, Xinghua; Kiryu-Seo, Sumiko; Kidd, Grahame J et al. (2015) Proteolipid protein cannot replace P0 protein as the major structural protein of peripheral nervous system myelin. Glia 63:66-77|
|Ohno, Nobuhiko; Chiang, Hao; Mahad, Don J et al. (2014) Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons. Proc Natl Acad Sci U S A 111:9953-8|
|Ohno, Nobuhiko; Kidd, Grahame J; Mahad, Don et al. (2011) Myelination and axonal electrical activity modulate the distribution and motility of mitochondria at CNS nodes of Ranvier. J Neurosci 31:7249-58|
|Zambonin, Jessica L; Zhao, Chao; Ohno, Nobuhiko et al. (2011) Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis. Brain 134:1901-13|
|Kiryu-Seo, Sumiko; Ohno, Nobuhiko; Kidd, Grahame J et al. (2010) Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport. J Neurosci 30:6658-66|
|Nave, Klaus-Armin; Trapp, Bruce D (2008) Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci 31:535-61|
|Yin, Xinghua; Baek, Rena C; Kirschner, Daniel A et al. (2006) Evolution of a neuroprotective function of central nervous system myelin. J Cell Biol 172:469-78|
|Kidd, Grahame J; Yadav, Vijay K; Huang, Ping et al. (2006) A dual tyrosine-leucine motif mediates myelin protein P0 targeting in MDCK cells. Glia 54:135-45|
|Avila, Robin L; Inouye, Hideyo; Baek, Rena C et al. (2005) Structure and stability of internodal myelin in mouse models of hereditary neuropathy. J Neuropathol Exp Neurol 64:976-90|
|Yin, Xinghua; Kidd, Grahame J; Pioro, Erik P et al. (2004) Dysmyelinated lower motor neurons retract and regenerate dysfunctional synaptic terminals. J Neurosci 24:3890-8|
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