ALS-linked SOD1 Mutants Enhance Outgrowth, Branching, and the Formation of Actin-Based Structures in Adult Motor Neurons

Abstract

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 adult SOD1 G93A mice have enhanced axonal outgrowth and dendritic branching. Further, the enhanced outgrowth occurs before the mice become symptomatic, but increases with disease progression. Motor neurons from SOD1 G93A mice also display an increase in the number and size of actin-based structures such as growth cones and filopodia. The increased outgrowth and branching phenotype is predominantly cellintrinsic and can be induced in motor neurons from non-transgenic mice by exogenous expression of SOD1 G93A . These results indicate that expression of mutant SOD1 in ALS-resistant adult motor neurons can enhance their regenerative capability via a mechanism that is not directly correlated with the onset of ALS symptoms. Understanding the positive effects that mutant SOD1 has on motor neuron regeneration could lead to new therapeutic strategies that capitalize on this mechanism.