Degeneration of spinal motor neurons in children leads to spinal muscular atrophy (SMA), the leading genetic cause of infant mortality. Although the genetic mutations that lead to SMA have been mapped to the Survival Motor Neuron 1 (SMN1) gene, mechanisms underlying spinal motor neuron degeneration in SMA remain largely unknown. Hence, there is no effective treatment for SMA. As part of my laboratory’s long-term goal of studying spinal motor neuron development and degeneration, this proposal aims to investigate a novel mechanism regulating the axonal transport of mitochondria transport and how dysregulation of this process leads to motor neuron degeneration in SMA. Findings from these studies will have broad implications for understanding neurodegenerative disorders and for developing new therapeutics. Using two SMA mouse models and human SMA induced pluripotent stem (iPS) cell-derived motor neurons, we found that the activity of cyclin-dependent kinase 5 (Cdk5) was significantly increased in motor neurons affected by SMA. Remarkably, pharmacological inhibition of the Cdk5 signaling pathway dramatically reduced motor neuron degeneration in human SMA iPS cell-derived motor neurons, suggesting a novel therapeutic strategy for SMA. Cdk5 phosphorylates histone deacetylase 5 (HDAC5) on serine 279 (S279) within its nuclear localization sequence (NLS), leading to increased cytoplasmic localization of HDAC5. Additionally, we also found that HDAC5 can deacetylate axon cytoskeletal tubulin to slow down retrograde axonal transport of mitochondria in SMA motor neurons. In this proposal, we plan to use a combination of genetic and biochemical approaches to investigate how the phosphorylation of HDAC5 S279 by Cdk5 regulates axonal transport, and how dysregulation of this mechanism leads to motor neuron degeneration in SMA. Studies will focus on the mechanisms regulating HDAC5 nuclear-cytoplasmic localization through Cdk5-mediated phosphorylation of S279. We will explore the role of HDAC5 phosphorylation in regulating axonal transport of mitochondria and motor neuron degeneration using SMA mouse and zebrafish models. We will also investigate the in vivo effect on rescuing SMA pathology by inhibiting the Cdk5-HDAC5 pathway in SMA mouse models. Altogether, findings from the proposed research will provide new insights into the mechanisms regulating axonal transport of mitochondria and motor neuron degeneration in SMA. These studies will likely facilitate the development of new diagnostic and therapeutic strategies for SMA and other neurodegenerative disorders.
|Effective start/end date||5/1/15 → 4/30/21|
- Hartwell Foundation (Award Letter 4/1/15)
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