Micro-RNA mediated regulation of neurodegeneration in Parkinson’s disease models
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Micro-RNA mediated regulation of neurodegeneration in Parkinson’s
disease models
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| Creator |
Bhattacharyya, Pallabi
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| Subject |
Cell Biology & Physiology
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| 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.
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| Date |
2022
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| 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. |
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| Relation |
http://www.eprints.iicb.res.in/2864/
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