Andersen Lab

Shankar J Chinta, PhD

Staff Scientist

schinta@buckinstitute.org

Research area: Cell death in Parkinson’s disease

Summary:

Oxidative stress, mitochondrial dysfunction, and α-synuclein oligomerization have all independently been implicated in the pathogenesis of Parkinson’s disease (PD). However, whether these factors act synergistically to contribute to subsequent neurotoxicity remain unclear. Previously, we have demonstrated that depletion of glutathione specifically within catecholaminergic neurons including those of the substantia nigra (SN) result in a selective mitochondrial complex I inhibition, followed by an age-related nigrostriatal neurodegeneration {Chinta et al., 2007}.

My current research goal is to understand how antioxidant glutathione depletion and mutations in α-synuclein or aberrant overexpression associated with PD converge on mitochondria to impact bioenergetic function, ROS production, and initiate downstream cascades that lead to the dismantling and loss of midbrain dopaminergic neurons in PD. By using newly generated inducible transgenic mouse models and various state-of-the-art biochemical techniques as well as mass spectrometric approaches, my research program will work toward identifying novel pathways and mechanisms involved in dopaminergic cell death towards the ultimate goal of novel drug discovery.

Publications:

1. Mallajosyula JK, Chinta SJ, Rajagopalan S, Nicholls DG, and Andersen JK. Metabolic Control Analysis in   a Cellular Model of Elevated MAO-B: Relevance to Parkinson’s Disease. Neurotoxicity Research 2009 Oct;16(3):186-93.

2. Chinta SJ, Rane A, Yadava N, Andersen JK, Nicholls DG, Polster BM. Reactive oxygen species regulation by AIF-and complex I-depleted brain mitochondria. Free Radic Biol Med. 2009 Apr 1; 46(7):939-47.

3. Chinta SJ, Rane A, Poksay KS, Bredesen DE, Andersen JK and Rao RV.  Coupling endoplasmic reticulum stress to the cell-death program in dopaminergic cells:  Effect of Paraquat. Neuromolecular Med. 2008; 10(4):333-42.

4. Chinta SJ, Andersen JK.  Redox imbalance in Parkinson's disease.  Biochim Biophys Acta. 2008 Nov;1780(11):1362-7.

5. Mallajosyula JK, Kaur D, Chinta SJ, Rajagopalan S, Rane A, Nicholls DG, Di Monte DA, Macarthur H, Andersen JK. MAO-B Elevation in Mouse Brain Astrocytes Results in Parkinson's Pathology.  PLoS ONE. 2008 Feb 20;3(2):e1616.

6. Chinta SJ, Kumar M J, Hsu M, Rajagopalan S, Kaur D, Rane A, Nicholls DG and Andersen JK. Inducible Depletion of Glutathione Within Adult Dopaminergic Midbrain Neurons Results in Selective Mitochondrial Complex I Inhibition and Age-Related Dopaminergic Nigrostriatal Neurodegeneration.  J Neurosci. 2007 Dec 19; 27(51):13997-4006.

7. Chinta SJ, Andersen JK. Reversible inhibition of mitochondrial complex I activity following chronic dopaminergic glutathione depletion in vitro: implications for Parkinson's disease. Free Radic Biol Med. 2006 Nov 1;41(9):1442-8.

8. Kaur D, Peng J, Chinta SJ, Rajagopalan S, Di Monte DA, Cherny RA & Andersen JK. Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Neurobiol Aging. 2007 Jun; 28(6):907-13.

9. Chinta SJ, Rajagopalan S, Butterfield DA, Andersen JK. In vitro and in vivo neuroprotection by gamma-glutamylcysteine ethyl ester against MPTP: Relevance to the role of glutathione in Parkinson's disease. Neurosci Lett. 2006 Jul 10; 402(1-2):137-41.

10. Chinta SJ, Kumar MJ, Zhang H, Forman HJ and Andersen JK. Up-regulation of γ-glutamyl transpeptidase (GGT) activity following GSH depletion has a compensatory rather than inhibitory effect on mitochondrial Complex I activity: implications for Parkinson’s disease. Free Radical Biology and medicine. 2006 May 1;40(9):1557-63.

11. Chinta, SJ, and Andersen, JK. Oxidant stress susceptibility of dopaminergic neurons: lessons from Parkinson’s disease. Cells in Focus review for special issue. Int J Biochem Cell Biol. 2005, 37(5):942-6.