The role of CNS Iron in Parkinson’s Disease

1. PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson The role of CNS Iron in Parkinson’s Disease Adam Abraha, Saliha Syeda, Sara Temkit, Leyla Warsame November 6, 2013

2. What is Parkinsons’s Disease? • Parkinson’s disease is a neurodegenerative disorder that is the result of the atrophy of neuron cells that produce dopamine in the CNS. • It is the 2nd most common neurological disease after Alzheimer’s • It is a progressive disease that manifests as tremors which results in increasing difficulty to control motor function • There is currently no cure for Parkinson’s disease

3. Who Does Parkinson’s Affect? • Generally affects the elderly, specifically people over the age of 50 • The main risk factor of Parkinson’s disease is age. • Men are more likely to develop Parkinson’s than women • Can be induced by environmental factors such as: smoking, regular caffeine intake, pesticide exposures.

4. Human Studies • [Iron] in the brain changes over lifetime: highest at birth, ↓ during the 1st two postnasal weeks, ↑ again during death • Even though there is a natural ↑in CNS [iron], PD shown to have extensive iron deposits • Post-mortem Studies & Imaging studies have shown ↑ iron in PD compared to controls • Males are actually at a higher risk than females. One Reason: Menstruation is protective • Fewer menses or greater lifetime exposure to iron—increases the risk of PD. Substantia niagra-SN, Caudate nucleus –CN, Globus pallidus -GP

5. Animal Studies • Animal models that mimic pathological components of PD have been studied • Studies in Rats have shown reduction in dopamine levels associated with ↑ brain iron concentration • Mouse models have shown excess CNS iron correlated with↑ levels of oxidative stress • Another study in Mice showed 35% ↓ in striatal dopamine and impaired motor function • ↑SN iron in adult animals show motor dysfunctions • ↑SN iron concentration at 3 months with elevated markers of oxidative stress, and decreased striatum dopamine at 12, 16, 24 months, but not at 2 months Substantia niagra-SN, Caudate nucleus –CN, Globus pallidus -GP

6. Role of Iron in the Pathological Mechanisms of PD • 1. Iron Contributes to Lewy Body Formation • Abnormal protein aggregates develop inside nerve cells in PD • The primary constituent of Lewy Bodies is alpha-synuclein • Iron contributes to lewy body formation by inducing alpha-synuclein fibril formation • The 5’UTR of alpha-synuclein mRNA contains an IRE • Iron can bind to IRE-BP, liberating it from the 5’UTR of alpha-synuclein, allowing transcription of the alpha-synuclein

7. Role of Iron in the Pathological Mechanisms of PD 2. Iron Inhibits Ubiquitin-Proteosome System • Proteosomes normally degrade damaged/unneeded proteins • The targeted proteins are first ubiquitinated and then lysed • UPS inhibition can lead to alpha-synuclein accumulation • Iron chelators diminish drug-induced proteasome inhibition and loss of DAergic neurons

8. Role of Iron in the Pathological Mechanisms of PD 3. Iron plays role in Oxidative Stress • DA is capable of autooxidation in the presence of ROS • Autooxidation is the direct rxn with O2 to produce hydrogen peroxide • Iron(Fe2+) can increase the rate of DA autooxidation via the fenton reaction • More ROS ultimately lead to damage to mitochondrial and nuclear DNA, lipid peroxidation and protein aggregation (adducts). • Brain is known for high oxygen utilization and low regenerative capacity

9. To summarize the Biochemical Mechanisms: • Ironpromotes alpha-synuclein formation and DA autooxidation. • It increases alpha synuclein formation: • Increasing transcription (IRE-BP) • Decreasing degradation (UPS)

10. Putting it All Together Iron – increases alpha synuclein synthesis and protein adduct formation

11. Iron in Combination with Other Predictors of PD: Cigarette Smoking • Cigarette smoking associated with a lower risk of Parkinson’s Disease. • Strong protective association between PD and smoking. • Cigarette smoke may stimulate dopamine release and upregulate nicotinic receptors through nicotine. • Inhibit free radical damage to nigral cells through carbon monoxide. • Nicotine complexes strongly with iron. • Formation of 6-hydroxydopamine is decreased. • Caused by Fe2+ and H2O2 reacting with dopamine (Fenton Reaction). • [Iron] is decreased, oxidative stress in dopamine neurons is decreased.

12. Iron in Combination with Other Predictors of PD: Coffee Drinking • Components of coffee and tea tend to show antioxidant activity. • Caffeine causes oxygen radical production by binding to copper ions and reducing them. • Therefore, in the presence of high metal ion concentrations and caffeine it shows pro-oxidant activity. • Maillard reaction products when combined with iron, protect a DNA strand from breaking. • This shows that it protects against oxidative damage that would be caused by the Fenton reaction. • Coffee and tea make it hard for the intestine to absorb iron.

13. Iron in Combination with Other Predictors of PD: Pesticides • Paraquat is a herbicide that was studied. • Paraquat is a conversion product of MPTP. • MPTP is toxic and produces Parkinson like symptoms when injected. • Exposure of Paraquat leads to increased production of H2O2. • H2O2 reacts with neural Iron and produces reactive oxygen species (Fenton reaction). • Higher Iron levels make paraquat more toxic.

14. Summary • Parkinson’s is a progressive disease of the nervous system and very prevalent in the elderly population • It is caused by the destruction of dopamine producing neurons which leads to a decrease in the ability to maintain muscle and motor function • Human studies have shown that ↑ iron in substantia niagra have lead to the severity of PD • Animal studies have shown that ↑ iron in substantia niagra is associated with decreased striatal dopamine, disturbed motor functions and ↑ oxidative stress • Nicotine, caffeine and pesticides have been shown to play a role in the causation of Parkinson’s disease due to the creation of reactive metabolites

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