Enhanced Neurite Outgrowth and Regeneration in ALS Resistant Motor Neurons from SOD1 Mutant Mouse Models

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by motor neuron cell death and subsequent paralysis of voluntary muscles. Although ALS specifically affects motor neurons, some cells are resistant to disease progression. Most ALS studies have focused on the cellular mechanisms that cause loss of motor neuron viability. Less is known about the surviving neurons, and most of that information has come from gene expression profiling. In this study, we functionally characterize the surviving spinal motor neurons by culturing them from SOD1 ALS mouse models at various stages of disease progression. Surprisingly, we found that in comparison to non-transgenic controls, ALS resistant motor neurons from SOD1G93A mice have enhanced axonal outgrowth and dendritic branching. They also display an increase in the number and size of actin-based structures such as growth cones and filopodia. The most substantial increase in outgrowth occurs in a low-copy SOD1G93A model with delayed disease onset. This phenotype occurs independently of SOD1 enzymatic activity and is cell autonomous. Further, the enhanced outgrowth occurs before the mice become symptomatic, but increases with disease progression. These results indicate that ALS resistant motor neurons are primed for regeneration significantly before ALS symptoms are present. Understanding this mechanism of cellular resistance and increased axonal outgrowth could uncover new therapeutic targets for the treatment of ALS.