CNS Iron in Parkinson’s Disease PHM142 Fall 2016 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson CNS Iron in Parkinson’s Disease Bridgette Chan, Wilson Chan, Rohail malhi nawaz

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

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 http://neuropathology-web.org/chapter9/chapter9dPD.html

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

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: https://en.wikipedia.org/wiki/Tyrosine_hydroxylase

Uptake and Storage of Iron Iron uptake: transferrin Iron storage: ferritin Neuromelanin is another important iron storage protein Source: http://mol-biol4masters.masters.grkraj.org/html/Protein_Synthesis9-Regulation_of_Protein_Synthesis_at_mRNA_Level_files/image022.gif

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: https://www.hindawi.com/journals/ijcb/2012/983245/

Generation of Reactive Metabolites Fenton reaction Source: https://image.slidesharecdn.com/parkinson-141127004233-conversion-gate01/95/parkinsonism-overview-6-638.jpg?cb=1417049026

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, 110-117. doi:10.1016/j.saa.2015.01.081

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 https://www.nobelprize.org/nobel_prizes/medicine/laureates/2000/illpres/carlsson.html

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:10.1016/j.neuropharm.2017.09.023

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

References Athauda, D., & Foltynie, T. (2017). Protective effects of the GLP-1 mimetic exendin-4 in Parkinsons disease. Neuropharmacology, 1-11. doi:10.1016/j.neuropharm.2017.09.023 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), 120–121. http://doi.org/10.1002/mds.25334 Dopamine Signaling in Parkinson's Disease Interactive Pathway. (n.d.). Retrieved November 04, 2017, from https://www.cellsignal.com/contents/science-cst- 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), a008888. http://doi.org/10.1101/cshperspect.a008888 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:10.1038/s41598-017-01402-2 Mochizuki, H., & Yasuda, A. (2012). Iron accumulation in Parkinson's disease. Journal of Neural Transmission, 119(12), 1511-1514. doi: 10.1007/s00702-012-0905-9 Mounsey, R.B. & Teismann, P. (2012). Chelators in the Treatment of Iron Accumulation in Parkinson's Disease. International Journal of Cell Biology, vol. 2012, a983245. doi:10.1155/2012/983245 Non-Motor Symptoms. (2017, September 27). Retrieved November 04, 2017, from http://www.parkinson.org/Understanding-Parkinsons/Non-Motor-Symptoms 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, 110-117. doi:10.1016/j.saa.2015.01.081 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 983245, 12 pages, 2012. doi:10.1155/2012/983245