Multiple checkpoints of protein clearance machinery are modulated by a common microRNA, miR-4813-3p, through its
Arunabh Sarkar1, Shamsuzzama1, Lalit Kumar1
1Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow, UP, India.
Abstract:
In order to maintain cellular homeostasis and a healthy state, aberrant and aggregated proteins are to be recognized and rapidly cleared from cells. Parkinson's disease, known to be associated with multiple factors; presents with impaired clearance of aggregated alpha synuclein as a key factor. We endeavored to study microRNA molecules with potential role on regulating multiple checkpoints of protein quality control within cells. Carrying out global miRNA profiling in a transgenic C. elegans model that expresses human alpha synuclein, we identified novel miRNA, miR-4813-3p, as a significantly downregulated molecule. Further studying its putative downstream target genes, we were able to mechanistically characterize six genes gbf-1, vha-5, cup-5, cpd-2, acs-1 and C27A12.7, which relate to endpoints associated with alpha synuclein expression, oxidative stress, locomotory behavior, autophagy and apoptotic pathways. Our study reveals the novel role of miR-4813-3p and provides potential functional characterization of its putative target genes, in regulating the various pathways associated with PQC network. miR-4813-3p modulates ERUPR, MTUPR, autophagosome-lysosomal-pathway and the ubiquitin-proteasomal-system, making this molecule an interesting target for further studies towards therapeutically addressing multifactorial aspect of Parkinson's disease.
Insights
Researchers identified a new microRNA, miR-4813-3p, that is downregulated in Parkinson's disease models. This microRNA regulates protein clearance pathways, offering a potential therapeutic target for Parkinson's disease.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Cellular homeostasis requires efficient clearance of aggregated proteins.
- Parkinson's disease is linked to impaired clearance of aggregated alpha-synuclein.
- MicroRNAs (miRNAs) are key regulators of cellular processes, including protein quality control.
Purpose of the Study:
- To investigate miRNAs involved in regulating protein quality control (PQC) pathways.
- To identify novel miRNA candidates associated with alpha-synuclein aggregation.
- To characterize the functional role of identified miRNAs and their target genes in cellular health.
Main Methods:
- Global miRNA profiling in a transgenic C. elegans model expressing human alpha-synuclein.
- Bioinformatic analysis to identify putative downstream target genes of differentially expressed miRNAs.
- Mechanistic characterization of target genes related to protein aggregation, oxidative stress, behavior, and apoptosis.
Main Results:
- miR-4813-3p was identified as a significantly downregulated miRNA in the Parkinson's disease model.
- Six target genes (gbf-1, vha-5, cup-5, cpd-2, acs-1, C27A12.7) were mechanistically characterized.
- miR-4813-3p was shown to modulate endoplasmic reticulum unfolded protein response (ERUPR), mitochondrial unfolded protein response (MTUPR), autophagy, and the ubiquitin-proteasomal system.
Conclusions:
- miR-4813-3p plays a novel role in regulating the protein quality control network.
- The identified target genes are involved in critical cellular pathways affected in Parkinson's disease.
- miR-4813-3p represents a potential therapeutic target for addressing Parkinson's disease pathogenesis.
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