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Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes
Ana Rita Vaz1,2, Daniela Vizinha1, Hermes Morais1
1Neuroinflammation, Signaling and Neuroregeneration Group, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
Abstract:
miRNA(miR)-124 is an important regulator of neurogenesis, but its upregulation in SOD1G93A motor neurons (mSOD1 MNs) was shown to associate with neurodegeneration and microglia activation. We used pre-miR-124 in wild-type (WT) MNs and anti-miR-124 in mSOD1 MNs to characterize the miR-124 pathological role. miR-124 overexpression in WT MNs produced a miRNA profile like that of mSOD1 MNs (high miR-125b; low miR-146a and miR-21), and similarly led to early apoptosis. Alterations in mSOD1 MNs were abrogated with anti-miR-124 and changes in their miRNAs mostly recapitulated by their secretome. Normalization of miR-124 levels in mSOD1 MNs prevented the dysregulation of neurite network, mitochondria dynamics, axonal transport, and synaptic signaling. Same alterations were observed in WT MNs after pre-miR-124 transfection. Secretome from mSOD1 MNs triggered spinal microglia activation, which was unno-ticed with that from anti-miR-124-modulated cells. Secretome from such modulated MNs, when added to SC organotypic cultures from mSOD1 mice in the early symptomatic stage, also coun-teracted the pathology associated to GFAP decrease, PSD-95 and CX3CL1-CX3CR1 signaling im-pairment, neuro-immune homeostatic imbalance, and enhanced miR-124 expression levels. Data suggest that miR-124 is implicated in MN degeneration and paracrine-mediated pathogenicity. We propose miR-124 as a new therapeutic target and a promising ALS biomarker in patient sub-populations.
Insights
MicroRNA-124 (miR-124) upregulation drives motor neuron degeneration and microglia activation in ALS. Normalizing miR-124 levels in motor neurons prevents these pathological changes, suggesting miR-124 as a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNA-124 (miR-124) is crucial for neurogenesis.
- Upregulation of miR-124 in SOD1G93A motor neurons (mSOD1 MNs) correlates with neurodegeneration and microglia activation.
- The precise pathological role of miR-124 in motor neuron disease remains to be fully elucidated.
Purpose of the Study:
- To investigate the pathological role of miR-124 in motor neuron degeneration.
- To explore miR-124 as a potential therapeutic target and biomarker for Amyotrophic Lateral Sclerosis (ALS).
Main Methods:
- Overexpression of pre-miR-124 in wild-type (WT) MNs and inhibition of miR-124 using anti-miR-124 in mSOD1 MNs.
- Analysis of miRNA profiles, apoptosis, neurite network, mitochondrial dynamics, axonal transport, and synaptic signaling.
- Assessment of secretome-mediated effects on spinal microglia activation and organotypic cultures.
Main Results:
- miR-124 overexpression in WT MNs mimicked the miRNA profile and induced apoptosis seen in mSOD1 MNs.
- Inhibition of miR-124 in mSOD1 MNs reversed neurodegenerative alterations and normalized miRNA profiles.
- Secretome from mSOD1 MNs activated microglia, an effect abrogated by anti-miR-124 treatment.
- Modulated MN secretome counteracted ALS pathology in organotypic cultures.
Conclusions:
- miR-124 plays a significant role in motor neuron degeneration and ALS pathogenesis.
- miR-124 contributes to neuroinflammation and pathogenicity through paracrine mechanisms.
- miR-124 is a potential therapeutic target and a promising biomarker for specific ALS patient populations.
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