International Journal of Molecular Sciences, Vol.10, No.3, 1226-1260, 2009
Physiological and Pathological Role of Alpha-synuclein in Parkinson's Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element
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 (alpha-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 alpha- syn oligomerization during PD pathology. Also, alpha-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;alpha-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).