Selective Motor Neuron Resistance and Recovery in a New Inducible Mouse Model of TDP-43 Proteinopathy.

Unlabelled: Motor neurons (MNs) are the neuronal class that is principally affected in amyotrophic lateral sclerosis (ALS), but it is widely known that individual motor pools do not succumb to degeneration simultaneously. Because >90% of ALS patients have an accumulation of cytoplasmic TDP-43 aggregates in postmortem brain and spinal cord (SC), it has been suggested that these inclusions in a given population may trigger its death. We investigated seven MN pools in our new inducible rNLS8 transgenic (Tg) mouse model of TDP-43 proteinopathy and found striking differences in MN responses to TDP-43 pathology. Despite widespread neuronal expression of cytoplasmic human TDP-43, only MNs in the hypoglossal nucleus and the SC are lost after 8 weeks of transgene expression, whereas those in the oculomotor, trigeminal, and facial nuclei are spared. Within the SC, slow MNs survive to end stage, whereas fast fatigable MNs are lost. Correspondingly, axonal dieback occurs first from fast-twitch muscle fibers, whereas slow-twitch fibers remain innervated. Individual pools show differences in the downregulation of endogenous nuclear TDP-43, but this does not fully account for vulnerability to degenerate. After transgene suppression, resistant MNs sprout collaterals to reinnervate previously denervated neuromuscular junctions concurrently with expression of matrix metalloproteinase 9 (MMP-9), a marker of fast MNs. Therefore, although pathological TDP-43 is linked to MN degeneration, the process is not stochastic and mirrors the highly selective patterns of MN degeneration observed in ALS patients.

Significance Statement: Because TDP-43 is the major pathological hallmark of amyotrophic lateral sclerosis (ALS), we generated mice in which mutant human TDP-43 expression causes progressive neuron loss. We show that these rNLS8 mice have a pattern of axonal dieback and cell death that mirrors that often observed in human patients. This finding demonstrates the diversity of motor neuron (MN) populations in their response to pathological TDP-43. Furthermore, we demonstrate that resistant MNs are able to compensate for the loss of their more vulnerable counterparts and change their phenotype in the process. These findings are important because using a mouse model that closely models human ALS in both the disease pathology and the pattern of degeneration is critical to studying and eventually treating progressive paralysis in ALS patients.