Rescuing Motor Neuron Mitochondrial Defects in SMA by Mitigating Cdk5 Activation Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is characterized by cellular defects lading to spinal motor neuron degeneration. Mechanisms underlying motor neuron degeneration in SMA remain largely unknown. Currently, effective treatments to prevent, halt or reverse this devastating disorder are not available. We recently identified a critical role for mitochondrial defects and increased oxidative stress in inducing motor neuron degeneration in mouse models of SMA. This proposal aims to investigate a novel mechanism underlying mitochondrial dysfunction and motor neuron degeneration in SMA, as well as a new treatment strategy. Using two different SMA mouse models, human SMA induced pluripotent stem (iPS) cell-derived motor neurons, and human SMA patient spinal cord samples, we observed that the activity of cyclin- dependent kinase 5 (Cdk5) was significantly increased in motor neurons affected by SMA. Notably, pharmacological inhibition of the Cdk5 signaling pathway dramatically reduces motor neuron degeneration in human SMA iPS cell-derived motor neurons, suggesting a novel therapeutic strategy. In addition, we found that Cdk5-mediated phosphorylation of microtubule-associated protein tau was significantly increased in SMA patients and mouse models. We also observed that the GTPase activity of mitochondrial fission protein Drp1 was significantly elevated in motor neurons affected by SMA. In this proposal, we plan to use a combination of genetic, cell biological and biochemical approaches to investigate how increased Cdk5 activity and its hyperphosphorylation of tau lead to mitochondrial defects, oxidative stress and motor neuron degeneration in SMA by dysregulating Drp1 activity and mitochondrial fission. We will also test mitigating aberrant Cdk5 activation and restoring mitochondrial bioenergetics as a therapeutic strategy for rescuing motor neuron defects in SMA mouse models in vivo. Successful completion of the proposed research will provide insights into the mechanisms regulating mitochondrial defects and motor neuron degeneration in SMA. These studies will likely facilitate the development of new therapeutic strategies for SMA and other neurodegenerative disorders.
Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, affecting approximately one in every six thousand live births. This proposal aims to explore a novel mechanism regulating motor neuron degeneration in SMA that involves the aberrant activation of cyclin-dependent kinase 5 (Cdk5), its phosphorylation of microtubule-associated protein tau, and mitochondrial defects. These studies will facilitate the development of new therapeutic approaches for SMA and other neurodegenerative disorders.
