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.

Public Health Relevance

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 mitochondrial functions, and how dysregulation of this mechanism leads mitochondrial oxidative stress and motor neuron degeneration in SMA. These studies will facilitate the development of new therapeutic approaches for SMA and other neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094564-04
Application #
9536164
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Nuckolls, Glen H
Project Start
2015-09-01
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Children's Memorial Hospital (Chicago)
Department
Type
DUNS #
074438755
City
Chicago
State
IL
Country
United States
Zip Code
60611
Edens, Brittany M; Yan, Jianhua; Miller, Nimrod et al. (2017) A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis. Elife 6:
Shi, Han; Deng, Han-Xiang; Gius, David et al. (2017) Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet 26:1915-1926
Deng, Han-Xiang; Shi, Yong; Yang, Yi et al. (2016) Identification of TMEM230 mutations in familial Parkinson's disease. Nat Genet 48:733-9
Edens, Brittany M; Miller, Nimrod; Ma, Yong-Chao (2016) Impaired Autophagy and Defective Mitochondrial Function: Converging Paths on the Road to Motor Neuron Degeneration. Front Cell Neurosci 10:44
Miller, Nimrod; Shi, Han; Zelikovich, Aaron S et al. (2016) Motor neuron mitochondrial dysfunction in spinal muscular atrophy. Hum Mol Genet 25:3395-3406