High content image analysis reveals function of miR-124 upstream of Vimentin in regulating motor neuron mitochondria

Yardeni, Tal; Fine, Raquel; Joshi, Yuvraj; Gradus-Pery, Tal; Kozer, Noga; Reichenstein, Irit; Yanowski, Eran; Nevo, Shir; Weiss-Tishler, Hila; Eisenberg-Bord, Michal; Shalit, Tal; Plotnikov, A.N.; Barr, Haim; Perlson, Eran; Hornstein, Eran

doi:10.1038/s41598-017-17878-x

Cited by 26 publications

(22 citation statements)

References 72 publications

(81 reference statements)

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“…To better understand the consequences of miR-124 differential expression in MN vitality, we next assessed changes in dendritic arborization, as well as in the expression of vimentin, a neurofilament subunit [ 37 ] and a direct target of miR-124 [ 20 ], together with the perturbation of synaptic and axonal transport dynamics. We observed that both pre-miR-124-treated WT cells and mSOD1 MNs have longer primary neurites, but reduced number of ramifications (at least p < 0.05 vs. WT MNs, Figure 3 a–c).…”

Section: Resultsmentioning

confidence: 99%

“…In a recent paper, mutant SOD1 MNs resistant to disease development showed enhanced axonal outgrowth and dendrite branching [ 67 ], which may represent a compensatory mechanism in cytoskeletal regulation, though we only observed for the neurite length. Intriguingly, the intermediate filament vimentin that is associated to neurite outgrowth [ 20 ] and a target of miR-124 [ 20 , 38 ], showed to be decreased when miR-124 was upregulated, but normal with anti-miR-124 modulation. Other factors accounting for reduced branching by miR-124 upregulation may derive from miR-146a downregulation and its known influence on the cytoskeleton actin through ROCK1 [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the same study, miR-124 was downregulated in neural stem cells from mSOD1 mice, but upregulated in differentiated MNs, suggesting its involvement in cellular differentiation. miR-124 overexpression also revealed to have a negative impact on MN morphology and mitochondrial activity, where vimentin was identified as a direct target [ 20 ]. These authors suggested that miR-124 expression should then be kept within defined limits.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes

Vaz

Vizinha

Morais

et al. 2021

IJMS

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes

Vaz

Vizinha

Morais

et al. 2021

IJMS

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“…As latent variable models and network models are mathematically equivalent, examining the eigenvalues of components present in data using exploratory factor analysis is one way to identify how many communities might be present and the factor loadings indicate which nodes belong to which community. More sophisticated approaches include the spinglass algorithim (although this is limited by the fact that it often produces different results every time you run it, and it only allows nodes to be part of one community, whereas nodes may be better described as belonging to several communities at the same time), the walktrap algorithim (which provides more consistent results if you repeat it, but which also only allows nodes to be part of one community), and the Clique Percolation Method (CPM), which allows nodes to belong to more than one community (see Blanken et al., 2018 ).…”

Section: Centralitymentioning

confidence: 99%

Network analysis: a brief overview and tutorial

Hevey

2018

Health Psychology and Behavioral Medicine

523

409

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Objective: The present paper presents a brief overview on network analysis as a statistical approach for health psychology researchers. Networks comprise graphical representations of the relationships (edges) between variables (nodes). Network analysis provides the capacity to estimate complex patterns of relationships and the network structure can be analysed to reveal core features of the network. This paper provides an overview of networks, how they can be visualised and analysed, and presents a simple example of how to conduct network analysis in R using data on the Theory Planned Behaviour (TPB). Method: Participants (n = 200) completed a TPB survey on regular exercise. The survey comprised items on attitudes, normative beliefs, perceived behavioural control, and intentions. Data were analysed to examine the network structure of the variables. The EBICglasso was applied to the partial correlation matrix. Results: The network structure reveals the variation in relationships between the items. The network split into three distinct communities of items. The affective attitude item was the central node in the network. However, replication of the network in larger samples to produce more stable and robust estimates of network indices is required. Conclusions: The reported network reveals that the affective attitudinal variable was the most important node in the network and therefore interventions could prioritise targeting changing the emotional responses to exercise. Network analysis offers the potential for insight into structural relations among core psychological processes to inform the health psychology science and practice.

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“…Conversely, miR-338 has a documented function in regulating oxidative phosphorylation, as well as the expression of mitochondrial proteins such as cytochrome C (Aschrafi et al, 2008 , 2012 ). Recently, miR-124 has been shown to regulate mitochondrial activity and localization in MNs (Yardeni et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Localization of RNAi Machinery to Axonal Branch Points and Growth Cones Is Facilitated by Mitochondria and Is Disrupted in ALS

Gershoni-Emek

Altman

Ionescu

et al. 2018

Front. Mol. Neurosci.

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Local protein synthesis in neuronal axons plays an important role in essential spatiotemporal signaling processes; however, the molecular basis for the post-transcriptional regulation controlling this process in axons is still not fully understood. Here we studied the axonal mechanisms underlying the transport and localization of microRNA (miRNA) and the RNAi machinery along the axon. We first identified miRNAs, Dicer, and Argonaute-2 (Ago2) in motor neuron (MN) axons. We then studied the localization of RNAi machinery and demonstrated that mitochondria associate with miR-124 and RNAi proteins in axons. Importantly, this co-localization occurs primarily at axonal branch points and growth cones. Moreover, using live cell imaging of a functional Cy3-tagged miR-124, we revealed that this miRNA is actively transported with acidic compartments in axons, and associates with stalled mitochondria at growth cones and axonal branch points. Finally, we observed enhanced retrograde transport of miR-124-Cy3, and a reduction in its localization to static mitochondria in MNs expressing the ALS causative gene hSOD1G93A. Taken together, our data suggest that mitochondria participate in the axonal localization and transport of RNAi machinery, and further imply that alterations in this mechanism may be associated with neurodegeneration in ALS.

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High content image analysis reveals function of miR-124 upstream of Vimentin in regulating motor neuron mitochondria

Cited by 26 publications

References 72 publications

Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes

Overexpression of miR-124 in Motor Neurons Plays a Key Role in ALS Pathological Processes

Network analysis: a brief overview and tutorial

Localization of RNAi Machinery to Axonal Branch Points and Growth Cones Is Facilitated by Mitochondria and Is Disrupted in ALS

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