Intricate molecular interactions between neurons and supporting glia cells are essential for the rapid propagation of action potentials and form the basis for myelinated axons to achieve saltatory conduction. Previously, the cell surface adhesion molecule Neurofascin (Nfasc) has been shown to have a dual-role, essential to the establishment of axonal domains from both the glial and neuronal interface. While the neuron-specific isoform (NF186) is indispensable for clustering of voltage-gated sodium channels at nodes of Ranvier; the glial-specific isoform (NF155) is required for myelinating glial cells to organize the paranode. Although many studies have used mouse models during development to address the roles of NF155 and NF186 in assembling paranodes and nodes, respectively; researchers have only begun to elucidate their roles in the maintenance and long-term health of the myelinated axons. Furthermore, no studies have addressed their potential to reestablish disrupted molecular domains in adults. In this proposal, we seek to define the role of NF155 and NF186 in the maintenance and repair of molecular domains in myelinated axons. We hypothesize that loss of Nfasc from adults leads to a sequential disruption of molecular domains that is reversible during a critical time frame. The proposed studies utilize novel spatio-temporally controlled transgenic mouse models to genetically ablate Nfasc in adult mice and then to re-express Nfasc at various time points. These mice will be evaluated through a combination of immunohistochemical, biochemical, ultrastructual, electrophysiological, and behavioral techniques in the following specific aims:
Aim 1 : To ascertain the long-term consequences of disrupted paranodal axo-glial junctions and the potential to restore the paranodal domain in myelinated axons.
Aim 2 : To elucidate the sequence in which the molecular components at nodes of Ranvier disorganize and potentially reorganize in myelinated axons. This innovative approach will lead to a better understanding of the critical time frame in which axo-glial interactions can be repaired and could ultimately aid in the design of future therapies to restore demyelinated axons and increase mobility in demyelinating diseases, such as multiple sclerosis.
The proposed studies are particularly relevant to demyelinating diseases, which are the leading cause of non-injury related disability in young adults. In particularly, patients with inflammatory demyelinating disorders, including multiple sclerosis, have been found to have high levels of antibodies against both NF186 and NF155. These data suggest loss of Nfasc from established axonal domains can contribute to the destabilization of axonal domains and consequently myelinated axons. Therefore, characterizing the roles of NF155 and NF186 in the maintenance and reorganization of molecular domains along axons could provide valuable insight to design future treatment for demyelinating diseases, such as multiple sclerosis.
| Shi, Qian; Saifetiarova, Julia; Taylor, Anna Marie et al. (2018) mTORC1 Activation by Loss of Tsc1 in Myelinating Glia Causes Downregulation of Quaking and Neurofascin 155 Leading to Paranodal Domain Disorganization. Front Cell Neurosci 12:201 |
| Kunisawa, Kazuo; Shimizu, Takeshi; Kushima, Itaru et al. (2018) Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability. J Neurochem 147:395-408 |
| Saifetiarova, Julia; Liu, Xi; Taylor, Anna M et al. (2017) Axonal domain disorganization in Caspr1 and Caspr2 mutant myelinated axons affects neuromuscular junction integrity, leading to muscle atrophy. J Neurosci Res 95:1373-1390 |
