Systemic Analysis of miRNAs in PD Stress Condition: miR-5701 Modulates Mitochondrial-Lysosomal Cross Talk to Regulate Neuronal Death

摘要

Parkinson's disease (PD) is complex neurological disorder and is prevalent in the elderly population. This is primarily due to loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) region of the brain. The modulators of the selective loss of dopaminergic neurons in PD are still not well understood. The small non-coding RNAs specifically miRNAs fine-tune the protein levels by post-transcriptional gene regulation. The role of miRNAs in PD pathogenesis is still not well characterized. In the current study, we identified the miRNA expression pattern in 6-OHDA-induced PD stress condition in SH-SY5Y, dopaminergic neuronal cell line. The targets of top 5 miRNAs both up- and down regulated were analyzed by using StarBase. The putative pathways of identified miRNAs included neurotrophin signaling, neuronal processes, mTOR, and cell death. The level of miR-5701 was significantly downregulated in the presence of 6-OHDA. The putative targets of miR-5701 miRNA include genes involved in lysosomal biogenesis and mitochondrial quality control. The transfection of miR-5701 mimic decreased the transcript level of VCP, LAPTM4A, and ATP6V0D1. The expression of miR-5701 mimic induces mitochondrial dysfunction, defect in autophagy flux, and further sensitizes SH-SY5Y cells to 6-OHDA-induced cell death. To our knowledge, the evidence in the current study demonstrated the dysregulation of specific pattern of miRNAs in PD stress conditions. We further characterized the role of miR-5701, a novel miRNA, as a potential regulator of the mitochondrial and lysosomal function determining the fate of neurons which has important implication in the pathogenesis of PD.