To show that in the setting of TDP-43 mediated neurodegeneration, slow motor neurons are resistant to the axonal dieback that is responsible for dysfunction and later, paralysis in patients with ALS. We also show that slow motor neurons mediate functional recovery from disease in our mouse model of ALS.

To study this, we use an inducible mouse model of TDP-43 proteinopathy to model ALS. The model recapitulates the progressive, selective MN death, but can also be switched on/off. We use viral MN tracing, nerve injury, and cross-reinnervation surgery before ALS-like disease and after recovery and measure motor recovery via functional, electrophysiological, and histological investigations.

We show that a new set of MNs is responsible for recovery from disease, which is distinct from the original innervating motor pool. The identity of those MNs are the adjacent ‘slow’ MNs, whose NMJ connections are more resistant to disease and axonal dieback, even after being challenged by a second disease course. This suggests there is an intrinsic coping mechanism of slow MNs that persists even after innervating fast twitch muscles. Our results show that motor recovery is dependent on the type of MN innervating the respective muscles, and not based on the muscle’s fiber type composition. 

These findings improve our understanding of MN compensation and function in this deadly disease. If we can directly target disease etiology therapeutically in ALS patients, the plasticity of the lower motor system allows for the recovery of lost function.