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Int. J. Mol. Sci. 2009, 10(3), 1226-1260; doi:10.3390/ijms10031226

Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element

1
Neurochemistry Laboratory, Department of Psychiatry-Neuroscience, Massachusetts General Hospital (East), Harvard Medical School, CNY2, Building 149, Charlestown, MA 02129, USA
2
Laboratory for High Throughput Biology, Yale University School of Medicine, West Haven, CT 06516-7381, USA
3
Laboratory of Neuroscience, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA
*
Authors to whom correspondence should be addressed.
Received: 31 December 2008 / Revised: 3 March 2009 / Accepted: 11 March 2009 / Published: 17 March 2009
(This article belongs to the Special Issue Advances in Molecular Neuropathology)
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Abstract

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer's disease (AD) and represents a large health burden to society. Genetic and oxidative risk factors have been proposed as possible causes, but their relative contribution remains unclear. Dysfunction of alpha-synuclein (α-syn) has been associated with PD due to its increased presence, together with iron, in Lewy bodies. Brain oxidative damage caused by iron may be partly mediated by α-syn oligomerization during PD pathology. Also, α-syn gene dosage can cause familial PD and inhibition of its gene expression by blocking translation via a newly identified Iron Responsive Element-like RNA sequence in its 5’-untranslated region may provide a new PD drug target.
Keywords: PD: Parkinson's disease; AD: Alzheimer's disease; α-syn: alpha-synuclein; PLD2: phospholipase D2; CNS: central nervous system; ER: endoplasmatic reticulum; PM: plasmatic membrane; LBs: Lewy bodies; LNs: Lewy neurites; GCIs: glial cytoplasmic inclusions; DLB: dementia with Lewy Bodies; DA: dopamine; DAT: dopamine transporter; NAC: non-amyloidogenic component; 5-UTR: 5'-untranslated region; IRE: iron responsive element; IRPs: interacting binding proteins; wt: wild-type; ROS: reactive oxygen species; GSH: reduced gluthatione; 6-OHDA: 6-hydroxydopamine; MPTP: 1-methyl 4-phenyl 1; 2; 3; 6 tetrapyridine; TfR: transferrin receptor; TH: tyrosine hydroxylase; nt: nucleotide(s); aa: amino acid(s) PD: Parkinson's disease; AD: Alzheimer's disease; α-syn: alpha-synuclein; PLD2: phospholipase D2; CNS: central nervous system; ER: endoplasmatic reticulum; PM: plasmatic membrane; LBs: Lewy bodies; LNs: Lewy neurites; GCIs: glial cytoplasmic inclusions; DLB: dementia with Lewy Bodies; DA: dopamine; DAT: dopamine transporter; NAC: non-amyloidogenic component; 5-UTR: 5'-untranslated region; IRE: iron responsive element; IRPs: interacting binding proteins; wt: wild-type; ROS: reactive oxygen species; GSH: reduced gluthatione; 6-OHDA: 6-hydroxydopamine; MPTP: 1-methyl 4-phenyl 1; 2; 3; 6 tetrapyridine; TfR: transferrin receptor; TH: tyrosine hydroxylase; nt: nucleotide(s); aa: amino acid(s)
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Olivares, D.; Huang, X.; Branden, L.; Greig, N.H.; Rogers, J.T. Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element. Int. J. Mol. Sci. 2009, 10, 1226-1260.

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