Mitochondria Dysfunction in Parkinson’s Disease

1. PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson Mitochondria Dysfunction in Parkinson’s Disease Annie (Xinyi) An & Becca (Beini) Zhang Oct. 16. 2013

2. Overview of Parkinson’s Disease (PD) • Progressive neurodegenerative disease • Characterized by motor dysfunction and cognitive impairment • Affects 0.5% of the general population • Primarily 65 year old + • Exact cause is unknown: • Genetic, Environment Factors

3. Symptoms of PD

4. Pathology of PD • Nigrostriatal pathway • Transmit dopamine from substantia nigra → striatum • Involved with production of movement • Selective loss of dopamine producing neurons in the substantia nigra • Loss of muscle movement

5. Role of Mitochondria • Oxidative Phosphorylation • Purine Synthesis (CAC) • Calcium Signaling • Steroid Synthesis • Programmed Cell Death (Apoptosis)

6. Aetiology of PD Central Focus From: EMBO Review: Mitochondria dysfunction in Parkinson’s disease: molecular mechanisms and pathophysioloical consequences

7. Reactive Oxygen Species & PD • Byproducts of the E.T.C • when ROS production>ROS removal • ROS damage mtDNA and mt membrane • Reactive ROS oxidizes amino acids • Protein aggregation • Impairment of neuroprotective pathways (Parkin) • Activation of death pathways

8. Mitochondrial Theory of Aging • Mitochondria mediated apoptosis & Calcium Homeostasis: • ↑ ROS → ↑Ca2+ → ↓ATP Production → Apoptosis • With age, mitochondria function degrades • Increased production of ROS • Accumulation of mtDNA mutations • Vicious cycle of impairment • Ultimately leads to SNc DA neuron death • Theory of Aging is Controversial • Unclear of how ROS induce mtDNA mutations

9. Genetic Mutations: Parkin • Parkin (Ubiquin E3 Ligase) • Autosomal recessive parkinsonism (100+ mutations) • Primary function is to protect against cell death, particularly those induced by oxidative stress • Cysteine-rich domain is inactivated by severe oxidative stress • Protein is misfolded → loses function • Promote degradation of α-synuclein (component of Lewy bodies) • Parkin-deficient cells have increased vulnerability to stress-induced cell death

10. Genetic Mutations: PINK1 • PINK1 (kinase): • Autosomal recessive parkinsonism (30+ mutations) • Impaired kinase activity or reduced stability • Increase resistance to diverse cellular stressors in a kinase-dependent manner • Knockdown has been shown to induce mitochondrial oxidative stress: • autophagy • disregulate calcium homeostasis

11. Mitophagy: Parkin & PINK1 Removal of damaged mitochondria From: EMBO Review: Mitochondria dysfunction in Parkinson’s disease: molecular mechanisms and pathophysioloical consequences

12. Why SNc DA neurons? • High oxidative burden -> ROS • High influx of calcium • High Fe (Fenton rxn) • Low antioxidant capacity • Low levels of glutathione • Cytoplasmic dopamine is susceptible to oxidation • Combination of above factors and unknown factors contribute to their susceptibility

13. Summary Slide • Cause: Compromised Nigrostriatal pathway • Necessary for motor movement control (thalamus) • Has both genetic & environmental contributors • Classic Symptoms: Motor dysfunction • Mitochondria function is vital to the integrity of neurons • Oxidative phosphorylation is important to the large energy demand of the neuron • Involved in the maintenance of intracellular [Ca2+] • Regulation of apoptosis • Leaky mitochondria → Reactive oxygen species production • Misfolding of proteins → compromised integrity of mitochondria due to misfunction • Genetic mutations in mtDNA: misfolding of PINK1 & Parkin proteins → loses protective properties against ROS → cell death → etiology of PD • PINK1: kinase involved in a variety of pathways to resist ROS damage • PARKIN: ligase involved in the protesome degradation pathway • Both are involved in mitophagy (elimination of faulty mitochondria) • SNc DA are significantly more susceptible to mitchondria dysfunction: • + intracellular [Ca2+] • + cytoplasmic dopamine (neurotoxin) • ++ oxidative burden

14. Works Cited Brown MR, Sullivan PG, Geddes JW 2006. Synaptic mitochondria are more susceptible to Ca2+ overload than nonsynaptic mitochondria. J Biol Chem281: 11658–11668 Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ 2010. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468: 696–700. Sheehan JP, Swerdlow RH, Parker WD, Miller SW, Davis RE, Tuttle JB 1997.Altered calcium homeostasis in cells transformed by mitochondria from individuals with Parkinson's disease. J Neurochem 68: 1221–1233. Sherer TB, Betarbet R, Greenamyre JT 2002. Environment, mitochondria, and Parkinson's disease. Neuroscientist 8: 192–197. Sousa SC, Maciel EN, Vercesi AE, Castilho RF 2003. Ca2+-induced oxidative stress in brain mitochondria treated with the respiratory chain inhibitor rotenone. FEBS Lett 543: 179–183. St Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, et al. 2006. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127: 397–408. Swerdlow RH, Parks JK, Miller SW, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP Jr, Davis RE, Parker WD Jr 1996. Origin and functional consequences of the complex I defect in Parkinson's disease. Ann Neurol 40: 663–671. Szabadkai G, Simoni AM, Bianchi K, De Stefani D, Leo S, Wieckowski MR, Rizzuto R 2006. Mitochondrial dynamics and Ca2+ signaling. Biochim Biophys Acta 1763: 442–449. Wibom R, et al. 2004. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429: 417–423.