Exosome-derived miR-128 is decreased in Parkinson’s patient plasma that maintains synaptic integrity and protects against both intrinsic and extrinsic pathways of neuronal apoptosis in models of Parkinson’s disease

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder resulting mainly from the death of dopaminergic neurons and a consequent reduction of dopamine levels in the mid-brain. Although itis the second most prevalent neurodegenerative disease in the world, any effective cure or biomarkers for its early detection are not available till date. To address the issue, in this study we have focused on brain-enriched non-coding small RNAs called microRNAs (miRNAs) that regulate post-transcriptional gene expression and may be released into the circulating body fluids packaged into membrane-bound extracellular micro-vesicles called exosomes. We identified a particular brain- and neuron-enriched miRNA, miR-128, which was significantly altered in the exosomes derived from the PD patient plasma. This observation was also substantiated by bioinformatics-based data. Furthermore, mechanistic studies on neurotoxin (6-OHDA) based in vitro models revealed an integral role of miR-128 in preventing activation of the transcription factor FoxO3a, thereby inhibiting both the intrinsic and extrinsic pathways of apoptosis via down-regulating the pro-apoptotic proteins PUMA and FasL respectively. Known to be highly localized at the synapse, miR-128 was also instrumental in attenuating PD-associated dysregulation of synaptic proteins like PSD-95 and synaptophysin. Additionally, it helped to restore neurite lengths and mitochondrial health, thereby maintaining the overall integrity of neurons. Thus, our study depicts for the first time the mechanistic significance of the altered expression of brain-enriched miR-128 in the exosomes of PD patient plasma and we believe characterization of such exosomal brain-enriched miRNAs as miR-128, is the key to proper understanding, detection and diagnosis of degenerative brain disorders like PD.