Project Summary/Abstract
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.