1. CNS Iron in Parkinson’s Disease
PHM Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
CNS Iron in Parkinson’s Disease
Bridgette Chan, Wilson Chan, Rohail malhi nawaz

2. Parkinson’s Disease (PD)
Progressive degeneration of dopaminergic neurons in the CNS
Cardinal symptoms: tremor, rigidity, postural instability, bradykinesia
At the time of diagnosis…
Diagnosis: based on medical history, neurological exam, supporting criteria
Non-motor symptoms

3. Neuropathological Features of PD
Loss of dopaminergic neurons in the substantia nigra (SNc)
Lewy bodies
α-synuclein
Mitochondrial dysfunction
High concentration of iron in the SNc

4. Causes of Parkinson’s Disease
Idiopathic
Exposure to neurotoxins: MPTP, pesticides
Genetic mutation (PARK):
Recessive: PINK-1, Parkin
Dominant: SNCA (α-synuclein)

5. Iron in the CNS
Iron is normally present in the brain – it is a cofactor for tyrosine hydroxylase to convert tyrosine to L-DOPA
Iron dysregulation is frequently associated with neurodegenerative disease
Accumulation of iron in the substantia nigra – cause or effect?
Source:

6. Uptake and Storage of Iron
Iron uptake: transferrin
Iron storage: ferritin
Neuromelanin is another important iron storage protein
Source:

7. Consequences of Iron Accumulation
Multiple factors contribute to accumulation of iron
Excess free iron can be oxidized to form free radicals
Accumulation of α-synuclein  Lewy body formation
Source:

8. Generation of Reactive Metabolites
Fenton reaction
Source:

9. Treatment of Parkinson's disease using iron chelators
Iron chelators (Deferiprone) are able to cross the blood brain barrier, bind to labile iron and remove it
It does this without redistributing iron to different areas of the brain which could cause further side effects
Works primarily on iron bound to ferritin rather than bound to neuromelanin
Pragourpun, K., Sakee, U., Fernandez, C., & Kruanetr, S. (2015). Deferiprone, a non-toxic reagent for determination of iron in samples via sequential injection analysis. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 142, doi: /j.saa

10. L-DOPA
The most common current form of treatment for Parkinson’s Disease is with the administration of L-DOPA
L-DOPA elevates dopamine levels in all parts of the brain

11. New Research: Glucagon like peptide 1 (glp-1)
Mitochondrial abnormalities may be a contributing factor to the presence of PD
GLP-1 is an insulin like hormone that, in the brain, promotes neuronal growth and reduces free radical formation
Exenatide is used as a GLP-1 agonist as it has a longer half life
Athauda, D., & Foltynie, T. (2017). Protective effects of the GLP-1 mimetic exendin-4 in Parkinsons disease. Neuropharmacology, 1-11. doi: /j.neuropharm

12. Summary
PD is a neurodegenerative disease characterized by Lewy-bodies: proteinaceous clusters of alpha-synuclein and ubiquitin
The genes PINK-1 and Parkin, related to autosomal recessive PD, are involved in regulating mitochondria
Unknown if iron accumulation is a cause or effect of dopaminergic neuronal degeneration
Iron accumulation causes excess formation of free radicals, leading to:
Protein folding and aggregation
Lipid peroxidation
Mitochondrial dysfunction
DNA fragmentation
Activation of microglia & inflammation
The most common treatment for PD is L-DOPA which acts as a dopamine precursor to increase synaptic levels
Other upcoming research for new treatments include the use of iron chelators and GLP-1 agonists

13. References
Athauda, D., & Foltynie, T. (2017). Protective effects of the GLP-1 mimetic exendin-4 in Parkinsons disease. Neuropharmacology, doi: /j.neuropharm Barbeau, A. (1969). L-Dopa Therapy in Parkinson’s Disease: A Critical Review of Nine Years’ Experience. Canadian Medical Association Journal, 101(13), 59–68. Belujon, P., & Grace, A. A. (2013). L-DOPA treatment duration versus Parkinson’s Disease progression: The dorsal-ventral divide. Movement Disorders : Official Journal of the Movement Disorder Society, 28(2), 120– Dopamine Signaling in Parkinson's Disease Interactive Pathway. (n.d.). Retrieved November 04, 2017, from pathways-neuroscience/dopamine-signaling-in-parkinson-s-disease-interactive-pathway/pathways-park Klein, C., & Westenberger, A. (2012). Genetics of Parkinson’s Disease. Cold Spring Harbor Perspectives in Medicine, 2(1), a Martin-Bastida, A., Ward, R. J., Newbould, R., Piccini, P., Sharp, D., Kabba, C., Dexter, D. T. (2017). Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Scientific Reports, 7(1). doi: /s Mochizuki, H., & Yasuda, A. (2012). Iron accumulation in Parkinson's disease. Journal of Neural Transmission, 119(12), doi: /s Mounsey, R.B. & Teismann, P. (2012). Chelators in the Treatment of Iron Accumulation in Parkinson's Disease. International Journal of Cell Biology, vol. 2012, a doi: /2012/ Non-Motor Symptoms. (2017, September 27). Retrieved November 04, 2017, from Pragourpun, K., Sakee, U., Fernandez, C., & Kruanetr, S. (2015). Deferiprone, a non-toxic reagent for determination of iron in samples via sequential injection analysis. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 142, doi: /j.saa Ross B. Mounsey and Peter Teismann, “Chelators in the Treatment of Iron Accumulation in Parkinson's Disease,” International Journal of Cell Biology, vol. 2012, Article ID , 12 pages, doi: /2012/983245