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

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)