期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：51
页码：E8316-E8325
DOI：10.1073/pnas.1605210113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceClinical 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 ({gamma}-MNs), which innervate muscle spindles and regulate primary proprioceptive afferent (IA) feedback on alpha motor neurons (-MNs). Genetic evidence presented here implicates this major excitatory input in the selective degeneration of -MNs in ALS. Functional elimination of IA inputs or partial elimination of {gamma}-MNs is protective in superoxide dismutase-1 (SOD1) mutant mice, suggesting that surviving {gamma}-MNs contribute to -MN loss by increasing muscle afferent-mediated excitation. This study highlights the role of synaptic connectivity and circuit function in motor neuron disease. 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 (-MNs) and complete sparing of gamma MNs ({gamma}-MNs), which selectively innervate muscle spindles. Resistant {gamma}-MNs are distinct from vulnerable -MNs in that they lack synaptic contacts from primary afferent (IA) fibers. Elimination of these synapses protects -MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced IA activation by targeted reduction of {gamma}-MNs in SOD1G93A 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.
关键词：ALS ; motor neuron disease ; gamma motor neuron ; fusimotor
