Manganese exposure: Linking down-regulation of miRNA-7 and miRNA-433 with α-synuclein overexpression and risk of idiopathic Parkinson's disease

Abstract

Manganese is an essential trace element however elevated environmental and occupational exposure to this element has been correlated with neurotoxicity symptoms clinically identical to idiopathic Parkinson's disease. In the present study we chronically exposed human neuroblastoma SH-SY5Y cells to manganese (100μM) and carried out expression profiling of miRNAs known to modulate neuronal differentiation and neurodegeneration. The miRNA PCR array results reveal alterations in expression levels of miRNAs, which have previously been associated with the regulation of synaptic transmission and apoptosis. The expressions of miR-7 and miR-433 significantly reduced upon manganese exposure. By in silico homology analysis we identified SNCA and FGF-20as targets of miR-7 and miR-433. We demonstrate an inverse correlation in expression levels where reduction in these two miRNAs causes increases in SNCA and FGF-20. Transient transfection of SH-SY5Y cells with miR-7 and miR-433 mimics resulted in down regulation of SNCA and FGF-20 mRNA levels. Our study is the first to uncover the potential link between manganese exposure, altered miRNA expression and parkinsonism: manganese exposure causes overexpression of SNCA and FGF-20 by diminishing miR-7 and miR-433 levels. These miRNAs may be considered critical for protection from manganese induced neurotoxic mechanism and hence as potential therapeutic targets.

CircSNCA downregulation by pramipexole treatment mediates cell apoptosis and autophagy in Parkinson’s disease by targeting miR-7

“…MiR-7 was reported to bind the 3’ UTR of SNCA and inhibited its translation, which was confirmed in our study [ 20 ]. Tarale et al proved that the low level of miR-7 implied a higher risk of idiopathic PD [ 21 ]. Zhou et al suggested that miR-7 inhibited neuroinflammation in the pathogenesis of PD through targeting Nod-like receptors [ 22 ].…”

Overexpression of miR‐138‐5p suppresses MnCl2‐induced autophagy by targeting SIRT1 in SH‐SY5Y cells

“…In workers at an electric‐furnace steel plant, exposure to metal‐rich particulate matter was found to modify the expression of candidate miRNAs, which then leads to neurodegenerative diseases such as AD and PD . in vitro cells, Mn exposure was proved to upregulate the expression of α‐synuclein and fibroblast growth factor 20 by diminishing miR‐7 and miR‐433 levels, thereby increasing the risk of idiopathic Parkinson's disease . Another report also demonstrated that 73 kinds of miRNA expressions were altered following excessive Mn treatment .…”

“…Studies have shown that upregulation of autophagy exerts neuroprotective effect, whereas dysfunctional autophagy is closely related to neurodegenerative diseases . It has been demonstrated that Mn can activate autophagy by triggering extracellular regulatory protein kinase (ERK1/2) and c‐Jun N‐terminal kinase (JNK) or inhibiting Akt signaling pathway . Activation of autophagy and abnormal aggregation of α‐synuclein in the brain tissue were also detected after mice subcutaneously injected with MnCl 2 for 4 weeks.…”

Critical Windows for Associations between Manganese Exposure during Pregnancy and Size at Birth: A Longitudinal Cohort Study in Wuhan, China

“…Moreover, Mn deficiency has been related to impairments or dysfunctions in lipoprotein metabolism, insulin production, oxidant defense system, and growth factor metabolism (Keen et al. 1999; Tarale et al. 2018).…”