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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons (MNs), though it is recognized that glial cells, namely astrocytes and microglia, are involved in ALS pathogenesis and progression [1,2]
We have previously demonstrated that miR-124 is upregulated in NSC34 mutations in superoxide dismutase 1 (mSOD1) MNs [25]
MNs are implicated in cell pathological alterations and in dysregulated signaling events that lead to microglia activation and neuro-immune impaired interactions
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons (MNs), though it is recognized that glial cells, namely astrocytes and microglia, are involved in ALS pathogenesis and progression [1,2]. Mice carrying mutations in superoxide dismutase 1 (mSOD1) are the most used models to investigate ALS pathophysiology. They closely mimic ALS symptoms in humans, and distinct glial phenotypes and inflammatory-associated profiles were identified in these animals [3,4,5]. Neuronal degeneration in ALS is linked to mitochondrial dysfunction, endoplasmic reticulum stress, unfolded protein response malfunction, and autophagy impairment [6,7,8].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
