Yong-Chao Ma - US grants

DESCRIPTION (provided by applicant): Dopaminergic neuron degeneration leads to Parkinson's disease, which is highly prevalent in older adults. As the second most common neurodegenerative disease and the most common movement disorder, Parkinson's disease is characterized by the loss of ventral midbrain substantia nigra dopaminergic neurons that control movement, mood, and motivation. Most cases of Parkinson's disease are age-dependent and sporadic, with about 5% are familial. Oxidative stress, including that induced by environmental toxicant 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and herbicide Paraquat, has been demonstrated to contribute to dopaminergic neuron degeneration in sporadic Parkinson's disease. But the molecular mechanism underlying oxidative stress-induced dopaminergic neuron degeneration remains largely unknown. This proposal aims to use MPTP-treated mice as an oxidative stress-induced Parkinson's disease model, together with knockout mice and cultured dopaminergic neurons to elucidate how oxidative stress can induce dopaminergic neuron degeneration. Specifically, this proposal will focus on SIRT1, a NAD-dependent protein deacetylase that is a master regulator of stress response, and forkhead transcription factor FOXA2, which was recently shown to be specifically expressed in mouse ventral midbrain dopaminergic neurons regulating their survival and development. This proposal plans to characterize the deacetylation of FOXA2 by SIRT1 in response to oxidative stress in dopaminergic neurons, and to address questions including what sites does SIRT1 deacetylate FOXA2 in vivo, how do these deacetylation events affect FOXA2 activity, and whether SIRT1 is involved in regulating dopaminergic neuron degeneration in response to oxidative stress in vivo. Together, these studies will test the novel roles of SIRT1 and SIRT1-mediated deacetylation of FOXA2 in Parkinson's disease pathogenesis. Findings from the proposed research will also provide new insights into the molecular mechanism underlying oxidative stress-induced dopaminergic neuron degeneration, which will hopefully lead to new strategies to better diagnose and treat Parkinson's disease and other neurodegenerative disorders.

? DESCRIPTION (provided by applicant): Regulation of Mitochondrial Function and Motor Neuron Degeneration in SMA. Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is characterized by the degeneration of spinal motor neurons. 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 remain largely unknown. Currently, there is no effective treatment for SMA despite ongoing clinical trials. This proposal aims to investigate a novel mechanism regulating mitochondrial functions, and how dysregulation of this mechanism leads to mitochondrial oxidative stress and motor neuron degeneration in SMA. Findings from these studies will have broad implications for understanding neurodegenerative disorders and for developing therapeutic strategies. Using two SMA mouse models and human SMA patient spinal cord samples, we have found that the kinase activity of cyclin-dependent kinase 5 (Cdk5) and its phosphorylation of histone deacetylase 5 (HDAC5) on serine 279 (S279) is significantly increased in motor neurons affected by SMA, leading to increased cytoplasmic localization of HDAC5. We have also observed that HDCA5 deacetylates mitochondrial outer membrane-binding protein Miro, which regulates mitochondrial movement and clearance. Furthermore, we made novel findings that mitochondrial oxidative stress was dramatically increased while mitochondrial movement was reduced in SMA motor neurons. In this proposal, we plan to use a combination of mouse genetic, cell biological and biochemical approaches to investigate how Cdk5-mediated phosphorylation of HDAC5 S279 regulates mitochondrial function and how dysregulation of this mechanism leads mitochondrial oxidative stress and motor neuron degeneration in SMA. Specifically, we will 1) characterize the effects of HDAC5-mediated deacetylation on Miro functions; 2) elucidate the mechanisms by which mitochondrial functions are dysregulated in SMA; 3) investigate the role of Cdk5 signaling pathway in SMA pathogenesis in vivo. Findings from the proposed research will provide insights into mechanisms regulating mitochondrial function, oxidative stress and motor neuron degeneration in SMA. These studies will facilitate the development of new therapeutic strategies for SMA and other neurodegenerative disorders.