Investigation of axonal transport in primary motor neuron model of amytrophic lateral sclerosis

Axonal transport defects are believed to contribute to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Superoxide dismutase 1 (SOD1) mutant proteins have been shown to be the culprit in approximately one fifth of the familial ALS cases. Our previous studies found that mutant SOD1 interacted with axonal transport protein dynein and reduced the rate of retrograde axonal transport. In this study, we are investigating the axonal transport of specific organelles, for example mitochondria, in the presence of wild type or mutant SOD1. The experimental strategy is to coexpress fluorescence‐labeled mitochondria marker and wild type or mutant SOD1 in cultured primary mouse motor neuron using lentivirus. Theaxonal transport of mitochondria in the presence of wild type or mutant SOD1 will be monitored and analyzed using time‐lapse fluorescence microscopy. Besides SOD1, mutations in TAR binding protein 43 (TDP‐43) and fused in sarcoma (FUS) have also been reported to be involved in familial ALS pathogenesis. We will determine whether these ALS mutant proteins would interact with the axonal transport motor proteins, and whether they would influence axonal transport in primary mouse motor neuron. The purpose of our study is to identify the molecular and cellular pathways responsible for the axonal transport defects induced by ALS mutant proteins, providing potential new targets for ALS therapy development. Supported by NIH grants R01NS049126 and R21AG032567 to HZ, and NCRR COBRE grant P20RR020171.