Objective: To assess the therapeutic and diagnostic potential of microRNA (miR)-153 and miR-223 in mice and humans with parkinsonism.

Background: Dysregulated miRNAs play a major role in developmental brain disorders, normal aging and various neurodegenerative conditions, including Parkinson disease (PD). These short noncoding RNA species bind to the 3’ untranslated region (3’-UTR) of target genes, resulting in targeted mRNA cleavage and protein translation repression. A recent study employing miRNA microchip assays on HMOX1- and sham-transfected primary rat astroglia showed that altered expression profiles of salient miRNAs and their mRNA targets contribute to neural damage accruing from the overexpression of glial heme oxygenase-1 (HO-1). HO-1, a stress protein that catalyzes the conversion of heme to biliverdin, carbon monoxide and free ferrous iron, has been implicated in PD pathogenesis.

Method: The advent of parkinsonian transgenic GFAP.HMOX1 mice, engineered to overexpress the human HO-1 gene (HMOX1) in astrocytes between 8.5 and 19 months of age, has facilitated our investigation of key miRNAs implicated in PD. The latter include miRNAs impacting neurodegenerative processes (oxidative stress, apoptosis, autophagy) and, more specifically, the hallmarks of PD (dopaminergic neuron degeneration, alpha-synuclein aggregation). Expression levels were measured by reverse transcriptase, quantitative PCR in mouse brain tissue and serum as well as human saliva (unstimulated).

Results: Downstream of HO-1 overexpression, miR-153 and miR-223 were found to directly regulate alpha-synuclein. MiR-153 and miR-223 were significantly downregulated in GFAP.HMOX1 basal ganglia, correlating with increased alpha-synuclein mRNA and protein. Additionally, serum concentrations of both miRNAs progressively declined in the wild-type (WT) and GFAP.HMOX1 mice between 11 and 19 months of age. At each time point surveyed, circulating levels of miR-153 were significantly lower in TG animals compared to WT controls. Moreover, in a diagnostic trial (n = 166), miR-153 and miR-223 were similarly decreased in the saliva of human PD subjects compared to healthy controls.

Conclusion: These findings underscore HO-1-mediated perturbations in brain and peripheral miRNA expression profiles as a driver of PD neuropathology and implicate glial HO-1, miR-153 and miR-223 as potential diagnostic markers and targets for disease-modifying therapy in this condition.

« Back to 2019 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/role-of-microrna-153-and-223-in-parkinson-disease/