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 (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: 5-UTR: 5’-untranslated region; 6-OHDA: 6-hydroxydopamine; AD: Alzheimer’s disease; CNS: central nervous system; DA: dopamine; DAT: dopamine transporter; DLB: dementia with Lewy Bodies; ER: endoplasmatic reticulum; GCIs: glial cytoplasmic inclusions; GSH: reduced gluthatione; IRE: iron responsive element; IRPs: interacting binding proteins; LBs: Lewy bodies; LNs: Lewy neurites; MPTP: 1-methyl 4-phenyl 1, 2, 3, 6 tetrapyridine; NAC: non-amyloidogenic component; PD: Parkinson’s disease; PLD2: phospholipase D2; PM: plasmatic membrane; ROS: reactive oxygen species; TH: tyrosine hydroxylase; TfR: transferrin receptor; aa: amino acid(s); nt: nucleotide(s); wt: wild-type; α-syn: alpha-synuclein.

Figure 1.

Alpha-synuclein’s sequence and domains. Blue highlighted: four α-helices responsible for protein-membrane interactions. Red highlighted: NAC or non-Aβ (amyloidogenic) component of α-syn, responsible of protein-protein interactions. Yellow highlighted: the unstructured C-terminal domain. Exons that undergo alternative splicing are indicated in bold: exon 3 from codon 41 to 54 and exon 5 from codon 103 to 130. Mutations A30P, E46K and A53T are in bold and enhanced. The seven 11 aa repeats are shown between the square brackets.

Figure 2.

An RNA Stem loop is predicted within 5’ Untranslated region (5’UTR) of the Parkinson’s disease alpha synuclein (α-syn) transcript that is homologous to the Iron-responsive element (IRE) in H-ferritin mRNA. Panel A: The α-syn 5’UTR is encoded by exon-1 and exon-2 of the α-syn gene, which can be alternatively spliced to generate either a shorter exon-1/-2 transcript (Panel B upper transcript, [187]), or the alternatively spliced transcript (longer by 375 bases, Panel B lower transcript). Panel B: The alternatively spliced α-syn 5’UTR mRNAs. There is a predominant transcript that encodes a CAGUGU motif at the exon-1/exon-2 splice junction. Also present is the longer alternatively spliced α-syn mRNA variant (Lower transcript) that encodes exon-1 and exon-2 but includes 375 bases of sequences from intron-1. Panel C: Alignment of the α-syn 5’UTR from human, mouse and rat demonstrating the lack of an IRE homology in rodent IREs (in bold is the CAGUGN loop sequences of canonical IREs). Similar to the boxed alignment of the α-syn 5’CAGUGU3’ motif against the IREs of ferritin H- and L- chains (iron storage), ferroportin (iron transport), erythroid eALAS (heme synthesis) mRNAs [186]. Panel D: This α-syn 5’UTR stem loop (ΔG =53 kcal/mol) was predicted by the RNA/FOLD computer program. This α-syn stem loop resembles the classical IRE RNA stem loop (5’CAGUGN3’ loop motif) that controls iron-dependent L- & H-ferritin translation & transferrin receptor (TfR) mRNA stability.