Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/ijms22116128
Keywords
amyotrophic lateral sclerosis; inflamma-miRNAs; miR-124 modulation; motor neuron regeneration; motor neuron secretome; mSOD1 mice model; neuro-immune deregulation; paracrine signaling regulation; spinal microglia; spinal organotypic cultures
Funding
- Fundacao para a Ciencia e a Tecnologia (FCT) [PTDC/MED-NEU/31395/2017, UIDB/04138/2020, UIDP/04138/2020]
- Programa Operacional Regional de Lisboa
- Programa Operacional Competitividade e Internacionalizacao [LISBOA-01-0145-FEDER-031395]
- Research Program in ALS from Santa Casa da Misericordia de Lisboa (SCML), Portugal [ELA-2015-002]
- FCT [SFRH/BD/129586/2017]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/129586/2017] Funding Source: FCT
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miR-124 is an important regulator of neurogenesis, with its dysregulation associated with neurodegeneration. Targeting miR-124 levels can prevent dysfunction in neuronal network, mitochondria dynamics, axonal transport, and synaptic signaling. Additionally, miR-124 may play a role in activating spinal microglia through paracrine signaling, contributing to ALS pathology.
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.
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