The Inhibition of miR-873 Provides Therapeutic Benefit in a Lipopolysaccharide-Induced Neuroinflammatory Model of Parkinson’s Disease

Abstract

Background and Purpose. Alterations in cholesterol homeostasis have been reported in cell and animal models of Parkinson’s disease (PD), although there are inconsistent data about the association between serum cholesterol levels and risk of PD. Here, we investigated the effects of miR-873 on lysosomal cholesterol homeostasis and progressive dopaminergic neuron damage in a lipopolysaccharide-(LPS) induced model of PD. Experimental Approach. To evaluate the therapeutic benefit of the miR-873 sponge, rats were injected with a LV-miR-873 sponge or the control vector 3 days before the right-unilateral injection of LPS into the substantia nigra (SN) pars compacta, or 8 and 16 days after LPS injection. Normal SH-SY5Y cells or SH-SY5Y cells overexpressing α-synuclein were used to evaluate the distribution of α-synuclein and cholesterol in lysosomes and to assess the autophagic flux after miR-873 transfection or ABCA1 silencing. The inhibition of miR-873 significantly ameliorated the LPS-induced accumulation of α-synuclein and loss of dopaminergic neurons in the SN at the early stage. miR-873 mediated the inhibition of ABCA1 by LPS. miR-873 transfection or ABCA1 silencing increased the lysosomal cholesterol and α-synuclein levels, and decreased the autophagic flux. The knockdown of ABCA1 or A20, which are the downstream target genes of miR-873, exacerbated the damage to LPS-induced dopaminergic neurons. Conclusion and Implications. The results suggest that the inhibition of miR-873 may play a dual protective role by improving intracellular cholesterol homeostasis and neuroinflammation in PD. The therapeutic effects of the miR-873 sponge in PD may be due to the upregulation of ABCA1 and A20.

Thioketal-Based Electrochemical Sensor Reveals Biphasic Effects of l-DOPA on Neuroinflammation

“…Given the close association between neuroinflammation and exacerbated neuronal damage involving excess ROS, our sensor’s ability to probe and monitor ROS levels is highly relevant for understanding and treating neuroinflammation. We employed LPS, , a Gram-negative bacterial component known to induce inflammation, to create a human neuroblastoma cell (SH-SY5Y) model of neuroinflammation (Figure A). The induction of ROS production by LPS treatment was confirmed through a cell permeant fluorogenic dye, DCFH-DA, that reacts with ROS to form fluorescent dichlorofluorescein.…”

Experimental capture of miRNA targetomes: disease-specific 3′UTR library-based miRNA targetomics for Parkinson’s disease

“…A significantly reduced miR-133b level was also demonstrated in the plasma of PD patients and in different models mimicking a PD-like phenotype 33 , 43 – 45 . miR-873-5p has been previously described to be neuroprotective in a neuroinflammatory model of PD 34 .…”

“…Although miRNAs that regulate only small numbers of target genes in the dopamine and PD-associated pathways might be less relevant for these signaling pathways, these miRNAs might nevertheless impact the pathogenesis of the disease via other signaling pathways. The miR-873-5p, which has been primarily described as neuroprotective in the context of neuroinflammation, may regulate target genes directly associated with the PD-associated immune response 34 . Although our study focused on the generation of miRNA‒target gene networks in affected dopaminergic neurons, identifying target genes of miR-873-5p that are associated with the immune system could further help to elucidate the role of this miRNA in PD pathogenesis, especially in the context of neuroinflammation.…”

Competing endogenous RNA (ceRNA) networks in Parkinson's disease: A systematic review

“…It should be noted that the ABCA1/miR-873/A20 ceRNA axes can be used to target neuroinflammation. Inhibition of miR-873 through increased ABCA1 may play a dual protective role in PD as it induces intracellular cholesterol homeostasis and improves neuroinflammation (Wu et al, 2017 ).…”