Distinct roles for motor neuron autophagy early and late in the SOD1 G93A mouse model of ALS

Significance Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that leads to death of spinal motor neurons and paralysis. Genetic studies of ALS patients have identified mutations in autophagy(definition) pathway genes including p62 / SQSTM1 , OPTN , TBK1 , VCP , and C9ORF72 . However, the mechanisms by which these mutations cause ALS are not understood. Here we investigated the role of autophagy in a mouse model of ALS by specifically disrupting the critical autophagy gene Atg7 in motor neurons. We found that inhibition of autophagy in motor neurons accelerated disease onset but prolonged lifespan. This increase in longevity was associated with a reduction in glial inflammation and interneuron pathology, indicating a non–cell-autonomous role for motor neuron autophagy in disease pathogenesis.