Motor neuron (MN) degeneration commences at the neuromuscular junction (NMJ) in the SOD1 model of motor neuron disease (MND). The NMJ features 3 cell types present in close physical proximity: neuronal (motor terminal), terminal Schwann cell (TSC), and muscle fiber. In preliminary work, we found that TSCs and pre-terminal Schwann cells (SCs) in SOD1 mice rapidly disappear from denervated NMJs whereas wildtype (WT) TSCs remain at denervated NMJs and help guide reinnervation. This SOD1 abnormality can be expected to hinder or prevent reinnervation of denervated muscle fibers by surviving MNs and accelerate the development of weakness. We considered the possibility that SOD1 endplates vacated by SOD1 TSCs can be reoccupied by wildtype SCs. To test this, we used a syngeneic approach and grafted pre-degenerated WT peripheral nerves into SOD1 muscles that were experimentally denervated at the same time. Preliminary evidence shows that after 2 weeks, muscle reinnervation is more rapid and robust in the presence of grafts and resembles reinnervation in WT animals. Moreover, this innervation persists at longer, post-grafting intervals.
In Aim 1, we will extend the characterization of these long term effects and learn whether they are associated with reduced MN cell death and improved muscle and motor unit performance. In addition, we will determine whether WT grafts can improve or preserve muscle innervation during the natural disease course.
In Aim 2, we will graft primary cultured WT SC, fibroblasts (FB) and acellular WT nerves and learn which of these major graft components is responsible for WT nerve graft effects in denervated SOD1 muscle. Finally, the appearance of TSCs and distal SCs in SOD1 muscles soon after denervation suggests that cell death may be involved in their disappearance.
In Aim 3, we will use immunolabels for necrosis and apoptosis to learn whether SOD1 SCs experience cell death soon after denervation in order to gain clues about possible trigger mechanisms. We hope that this innovative use of grafting tissue/cells will produce new clues about possible therapies and extend understanding about how SCs contribute to MND in SOD1 mice.

Public Health Relevance

In preliminary studies, we found that Schwann cells that normally provide support for the motor terminal disappear after denervation of muscles in the SOD1 mouse model of motor neuron disease (MND). Preliminary studies also show that grafts of wildtype nerve markedly improve reinnervation of MND muscles and that the reinnervation persists at long intervals. The goals of the proposed studies are to determine the scope of these long term effects, to learn whether wildtype nerve grafts can improve muscle performance during the natural disease course, to learn which graft components are responsible for effects, to learn whether SOD1 Schwann cells undergo cell death after denervation and to determine the mode of cell death.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Gubitz, Amelie
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Emory University
Schools of Medicine
United States
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Carrasco, Dario I; Bahr, Ben A; Seburn, Kevin L et al. (2016) Abnormal response of distal Schwann cells to denervation in a mouse model of motor neuron disease. Exp Neurol 278:116-26