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Brain-enriched miR-128: Reduced in exosomes from Parkinson’s patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis

Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with the death of mid-brain dopaminergic neurons. Unfortunately, no effective cure or diagnostic biomarkers for PD are available yet. To address this, the present study focuses on brain-enriched small non-coding regulato...

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Autores principales: Bhattacharyya, Pallabi, Biswas, Atanu, Biswas, Subhas C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879011/
https://www.ncbi.nlm.nih.gov/pubmed/36713778
http://dx.doi.org/10.3389/fncel.2022.1037903
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author Bhattacharyya, Pallabi
Biswas, Atanu
Biswas, Subhas C.
author_facet Bhattacharyya, Pallabi
Biswas, Atanu
Biswas, Subhas C.
author_sort Bhattacharyya, Pallabi
collection PubMed
description Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with the death of mid-brain dopaminergic neurons. Unfortunately, no effective cure or diagnostic biomarkers for PD are available yet. To address this, the present study focuses on brain-enriched small non-coding regulatory RNAs called microRNAs (miRNAs) that are released into the circulation packaged inside small extracellular vesicles called exosomes. We collected blood samples from PD patients and isolated exosomes from the plasma. qPCR-based detection revealed a particular neuron-enriched miR-128 to be significantly decreased in the patient-derived exosomes. Interestingly, a concomitant decreased expression of miR-128 was observed in the cellular models of PD. Fluorescent live cell imaging and flow-cytometry revealed that over-expression of miR-128 can prevent 6-OHDA-mediated mitochondrial superoxide production and induction of neuronal death respectively. This neuroprotective effect was found to be induced by miR-128-mediated inhibition of FoxO3a activation, a transcription factor involved in apoptosis. miR-128 over-expression also resulted in down-regulation of pro-apoptotic FoxO3a targets- FasL and PUMA, at both transcript and protein levels. Further downstream, miR-128 over-expression inhibited activation of caspases-8, -9 and -3, preventing both the intrinsic and extrinsic pathways of apoptosis. Additionally, over expression of miR-128 prevented down-regulation of synaptic proteins- Synaptophysin and PSD-95 and attenuated neurite shortening, thereby maintaining overall neuronal integrity. Thus, our study depicts the intracellular role of miR-128 in neuronal apoptosis and neurodegeneration and its implications as a biomarker being detectable in the circulating exosomes of PD patient blood. Thus, characterization of such exosomal brain-enriched miRNAs hold promise for effective detection and diagnosis of PD.
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spelling pubmed-98790112023-01-27 Brain-enriched miR-128: Reduced in exosomes from Parkinson’s patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis Bhattacharyya, Pallabi Biswas, Atanu Biswas, Subhas C. Front Cell Neurosci Neuroscience Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with the death of mid-brain dopaminergic neurons. Unfortunately, no effective cure or diagnostic biomarkers for PD are available yet. To address this, the present study focuses on brain-enriched small non-coding regulatory RNAs called microRNAs (miRNAs) that are released into the circulation packaged inside small extracellular vesicles called exosomes. We collected blood samples from PD patients and isolated exosomes from the plasma. qPCR-based detection revealed a particular neuron-enriched miR-128 to be significantly decreased in the patient-derived exosomes. Interestingly, a concomitant decreased expression of miR-128 was observed in the cellular models of PD. Fluorescent live cell imaging and flow-cytometry revealed that over-expression of miR-128 can prevent 6-OHDA-mediated mitochondrial superoxide production and induction of neuronal death respectively. This neuroprotective effect was found to be induced by miR-128-mediated inhibition of FoxO3a activation, a transcription factor involved in apoptosis. miR-128 over-expression also resulted in down-regulation of pro-apoptotic FoxO3a targets- FasL and PUMA, at both transcript and protein levels. Further downstream, miR-128 over-expression inhibited activation of caspases-8, -9 and -3, preventing both the intrinsic and extrinsic pathways of apoptosis. Additionally, over expression of miR-128 prevented down-regulation of synaptic proteins- Synaptophysin and PSD-95 and attenuated neurite shortening, thereby maintaining overall neuronal integrity. Thus, our study depicts the intracellular role of miR-128 in neuronal apoptosis and neurodegeneration and its implications as a biomarker being detectable in the circulating exosomes of PD patient blood. Thus, characterization of such exosomal brain-enriched miRNAs hold promise for effective detection and diagnosis of PD. Frontiers Media S.A. 2023-01-12 /pmc/articles/PMC9879011/ /pubmed/36713778 http://dx.doi.org/10.3389/fncel.2022.1037903 Text en Copyright © 2023 Bhattacharyya, Biswas and Biswas. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Bhattacharyya, Pallabi
Biswas, Atanu
Biswas, Subhas C.
Brain-enriched miR-128: Reduced in exosomes from Parkinson’s patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis
title Brain-enriched miR-128: Reduced in exosomes from Parkinson’s patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis
title_full Brain-enriched miR-128: Reduced in exosomes from Parkinson’s patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis
title_fullStr Brain-enriched miR-128: Reduced in exosomes from Parkinson’s patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis
title_full_unstemmed Brain-enriched miR-128: Reduced in exosomes from Parkinson’s patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis
title_short Brain-enriched miR-128: Reduced in exosomes from Parkinson’s patient plasma, improves synaptic integrity, and prevents 6-OHDA mediated neuronal apoptosis
title_sort brain-enriched mir-128: reduced in exosomes from parkinson’s patient plasma, improves synaptic integrity, and prevents 6-ohda mediated neuronal apoptosis
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879011/
https://www.ncbi.nlm.nih.gov/pubmed/36713778
http://dx.doi.org/10.3389/fncel.2022.1037903
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