Parkinson’s Disease : A Malady arising due to Free radicals and

Mitochondrial disturbances£ Introduction.₹ Mitochondria : ROS, RNS site of generation.₳ Role of DJ1 – gene₢ Kynurenine Pathway₣ Drp1 gene₺ Overview of genes and Environmental factors involved₮ Diagnosis ₦ Flavinoids

Introduction• Progressive

Neurodegenerative disease of CNS that is chiefly restricted to Motor system.

• It is due to degeneration of Nigrostriatal tract which is the source of Dopamine.

• Classical hallmarks of Parkinson are

1. Lewy bodies2. Tau bodies.

Mitochondria: Site of ROS, RNS generation

(Phaniendra et al., 2015) (Kasthuri et. al.)

DJ-1 gene Also known as Park7

( Parkinson Disease protein 7). It is an Autosomal recessive version of PD causing gene.

Environmental toxins e.g. Herbicides and Pesticides are responsible for causing oxidative stress.

Studies indicate that DJ-1 gene is involved in the protection from oxidative stress caused due to these toxins.

(Phaniendra et al., 2015)

(Björkblom et al., 2016)

Kynurenine Metabolism

₪ Kynurenic Acid acts as a neuroprotective agent.

₪ However, Quinolinic Acid is a generator of free radical and as a result a potential neurotoxin.

₪ Studies from post-mortem suffering from PD illustrated following i. Low Quinolinic Acid

ii. High Kyunerinic Acid

₪ Clinical Treatment: Intracerebrovemtricular administration of Nicotinyl- alanine. It Inhibits Kynureninase and Kynureninine 3-hydroxylase which is responsible for the generation of Quinolinic Acid.

(Sas et al., 2007)

Dynamin Related Protein 1 gene (Drp1)

₣ Mitochondrial fission and fusion is governed by GTPases of the Dynamin superfamily.

₣ Drp1 is essential for the post-mitotic health of the neuron. Thus, its ablation will lead to the neurodegeneration caused due to oxidative stress.

₣ The consumption and ATP levels of the hippocampal mitochondria are significantly reduced in the neurons devoid/lacking proper amount of Drp1 gene.

₣ Moreover, Drp1 insufficiency leads to ROS production.

(Oettinghaus, B et al)

(Valko et al., 2007)

Fenton & Haber-WeissReaction• Known to generate Higher Oxidation states of Fe.• Makes Dopamine act like a chelator.

Diagnosis• Radionuclide best way to observe Dopamine deficiency.• PET and MRI for studying functional connectivity.

Flavonoids

Kasthuri et. al.

₲ It is observed to reduce the effect of MPTP (N-methyl-4-phenyl- 1, 2, 3,6 – tetrahydropyridine) which is a potent neurotoxin.

(Solanki et al., 2015)

Sources Jenner P, Dexter DT, Sian J, Schapira AH, Marsden CD (1992) Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson’s Disease Research Group. Ann Neurol 32 Suppl:S82–S87.

Phaniendra A, Jestadi DB, Periyasamy L (2015) Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases. Indian J Clin Biochem 30:11–26.

Sas K, Robotka H, Toldi J, Vécsei L (2007) Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J Neurol Sci 257:221–239.

Solanki I, Parihar P, Mansuri ML, Parihar MS (2015) Flavonoid-Based Therapies in the Early Management of Neurodegenerative Diseases. Adv Nutr Int Rev J 6:64–72.

Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84

Björkblom, Benny et al. “Parkinson Disease Protein DJ-1 Binds Metals and Protects against Metal-Induced Cytotoxicity.” The Journal of Biological Chemistry 288.31 (2013): 22809–22820. PMC. Web. 17 Apr. 2016.

Oettinghaus, B et al. “Synaptic Dysfunction, Memory Deficits and Hippocampal Atrophy due to Ablation of Mitochondrial Fission in Adult Forebrain Neurons.”Cell Death and Differentiation 23.1 (2016): 18–28. PMC. Web. 18 Apr. 2016.

http://www.bioscirep.org/content/ppbioscirep/26/5/341.full.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454525/pdf/nihms4603.pdf

Kasthuri Bai Magalingam, Ammu Kutty Radhakrishnan, and Nagaraja Haleagrahara, “Protective Mechanisms of Flavonoids in Parkinson’s Disease,” Oxidative Medicine and Cellular Longevity, vol. 2015