Examining neuronal resilience in a mouse model of sporadic ALS

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Project Summary/Abstract Following an injury to the brain, healthy neurons that are adjacent to the damaged area can sometimes take over the functions performed by the impaired neurons. This process has been best studied after acute nerve damage, but there is evidence that compensation by surviving neurons is also happening in the early stages of neurodegenerative diseases. In amyotrophic lateral sclerosis (ALS), the fiber type grouping in muscle samples taken from patients suggests that after an initial loss of connections between motor neurons (MNs) and muscles, new nerves are able to reconnect to allow patients to maintain movement during the disease process. A second observation made at the time of autopsy is that the vast majority of patients have an accumulation of a mislocalized protein called TDP-43 in the surviving MNs. However, because these cells are inaccessible in early disease stages, the molecular mechanisms for coping with disease processes in the MNs that send out new connections to muscles are unknown. In order to determine the dynamic responses that could allow a subpopulation of MNs to cope specifically with mislocalized TDP-43 and send out new axonal connections to muscles to prevent paralysis, we developed a mouse model in which we can induce neuronal expression of mislocalized human TDP-43, called rNLS8 mice. We then showed that rNLS8 mice have certain subsets of MNs that are uniquely vulnerable to disease, and that surviving MNs can effectively take the place of these cells, even late into the disease course. In this study, we will now identify the populations of MNs responsible for the reinnervation and restoration of function of vulnerable muscles after the initial TDP-43 triggered MN loss (Aim 1), using a combination of neuronal tracing techniques, muscle physiology, and imaging at the neuromuscular junction. We will then look for the upstream contribution of the brain's immune cells, microglia, to MN plasticity and the resultant circuit changes (Aim 2) by pharmacologically eliminating microglia and selectively reintroducing microglial derived factors that have been previously shown to influence neuronal function. Finally, molecular differences between MNs that innervate the same muscle before and after TDP-43 triggered axonal dieback will be uncovered by RNA- Sequencing and the top gene targets will be validated for their effect on motor function during ALS-like disease in rNLS8 mice (Aim 3). Completion of these studies should provide valuable insights into the potential mechanisms by which subsets of MNs can tolerate a build-up of cytoplasmic TDP-43. Moreover, understanding the mechanisms of neuronal compensation could allow for the development of therapies aimed at supporting surviving cells in order to extend their natural plasticity to slow disease and maintain function in patients.