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Micro-RNA mediated regulation of neurodegeneration in Parkinson’s disease models

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Title Micro-RNA mediated regulation of neurodegeneration in Parkinson’s
disease models
 
Creator Bhattacharyya, Pallabi
 
Subject Cell Biology & Physiology
 
Description microRNAs (miRNAs/miRs) are non-coding small RNAs that are important for post-transcriptional
gene regulation and maybe released from the parent cell packaged inside certain membrane-bound
extracellular microvesicles called exosomes. For my Ph.D. thesis, I have focused on brain-enriched
miRNAs- miR-128 (neuron-enriched) and miR-23a (astrocyte-enriched) and studied their role in PD
pathogenesis.
miR-128 is a neuron-enriched miRNA which was observed to be down-regulated in the cellular
models of PD under 6-OHDA treatment. miR-128 prevented activation of the transcription factor
FoXO3a and could regulate the expression of the downstream targets of FoXO3a- the pro-apoptotic
proteins PUMA and FasL. By down-regulating these proteins, miR-128 could successfully shutdown
both the intrinsic and extrinsic pathways of apoptosis. Additionally, miR-128 could prevent
mitochondrial superoxide generation. Furthermore, miR-128 overexpression inhibited 6-OHDA
induced neurite shortening and promoted neurite formation. Finally, miR-128 overexpression
improved synaptic health by up-regulating the expressions of synaptic proteins synaptophysin and
PSD-95. On the other hand, miR-23a is an astrocyte-enriched miRNA that was downregulated in astrocytes
upon Rotenone treatment. Interestingly, Rotenone treatment led to Ca2+ surge in the astrocytes,
followed by activation of the Ca2+/CaM dependent protein phosphatase, Calcineurin. Calcineurin
was also found to co-express in the reactive astrocytes of acute MPTP models of PD. Further
downstream of Calcineurin pathway, miR-23a underwent release from the astrocytes via exosomes.
This exosomal miR-23a proved to be neuroprotective in different neuronal models of PD. 3’UTR
cloning revealed that miR-23a can directly bind to and down-regulate the expression of proapoptotic
PUMA in the neuronal cells, thereby preventing induction of 6-OHDA mediated neuronal
apoptosis.
Finally, both miR-128 and miR-23a was found to be differentially expressed in the exosomes
derived from the PD patient plasma. This data was further validated from human sRNA-Seq data
obtained from miRNA expression and exosome repositories like DIANA-miTED and EVAtlas
respectively. Thus, brain-enriched miRNAs- miR-128 (neuron-enriched) and miR-23a (astrocyteenriched)
proved to play significant roles in the pathogenesis of PD and showed potential to be
important biomarkers and therapeutic targets for the detection, diagnosis and cure of PD.
 
Date 2022
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2864/1/THESIS%2D_PB_2022.pdf
Bhattacharyya, Pallabi (2022) Micro-RNA mediated regulation of neurodegeneration in Parkinson’s disease models. PhD thesis, JADAVPUR UNIVERSITY.
 
Relation http://www.eprints.iicb.res.in/2864/