title: Gamma motor neurons survive and exacerbate alpha motor neuron degeneration in ALS.
abstract: 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 (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (IA) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced IAactivation by targeted reduction of γ-MNs in SOD1G93Amutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-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.
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032.|Department of Neurology, Columbia University, New York, NY 10032.
authors.forename: Melanie
authors.initials: M
authors.lastname: Lalancette-Hebert
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032.|Department of Neurology, Columbia University, New York, NY 10032.
authors.forename: Aarti
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032.|Department of Neurology, Columbia University, New York, NY 10032.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Lyashchenko
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032; ns327@columbia.edu.|Department of Neurology, Columbia University, New York, NY 10032.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Shneider
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology*; D009047:Motor Neurons, Gamma / Q000166:cytology*; D009132:Muscles / Q000294:innervation; D009154:Mutation; D009475:Neurons, Afferent / Q000166:cytology; D011434:Proprioception; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1 / Q000235:genetics; D013569:Synapses / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ALS; fusimotor; gamma motor neuron; motor neuron disease