Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS

Significance Clinical and pathological hallmarks shared by various familial and sporadic forms of amyotrophic lateral sclerosis (ALS) suggest common underlying mechanisms of disease. Using a series of ALS mouse models, we demonstrate that one shared feature of ALS is the selective sparing of gamma motor neurons (γ-MNs), which innervate muscle spindles and regulate primary proprioceptive afferent (I A ) feedback on alpha motor neurons (α-MNs). Genetic evidence presented here implicates this major excitatory input in the selective degeneration of α-MNs in ALS. Functional elimination of I A inputs or partial elimination of γ-MNs is protective in superoxide dismutase-1 (SOD1) mutant mice, suggesting that surviving γ-MNs contribute to α-MN loss by increasing muscle afferent-mediated excitation. This study highlights the role of synaptic connectivity and circuit function in motor neuron disease.