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

The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (alpha-MNs) and complete sparing of gamma MNs (gamma-MNs), which selectively innervate muscle spindles. Resistant gamma-MNs are distinct from vulnerable alpha-MNs in that they lack synaptic contacts from primary afferent (I-A) fibers. Elimination of these synapses protects a-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced IA activation by targeted reduction of gamma-MNs in SOD1(G93A) mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving gamma-MNs in ALS. This study establishes the resistance of gamma-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.