Regulatory function of <scp>microRNAs</scp> in microglia

Brites, Dora

doi:10.1002/glia.23846

Cited by 46 publications

(58 citation statements)

References 135 publications

(151 reference statements)

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“…However, the molecular mechanisms underlying MN-glia deregulated paracrine signaling in ALS are not fully elucidated. In recent years, microRNAs (miRNAs), small noncoding RNAs, were described as active drivers in intercellular communication, as they affect gene expression in both donor and recipient cells [ 9 ]. miRNAs are released from cells into their secretome and circulate either as soluble molecules or as cargo in small extracellular vesicles with ~100 nm size, also called exosomes.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…miRNAs that initiate mRNA silencing and modulate mRNA stability have been implicated in the development of many neurological and other diseases, and constitute an attractive target for NBT-mediated manipulation. Both synthetic miRNA mimics (promiRs) and blockers (antagomirs or miRNA sponges) have been designed, although none of the clinical stage miRNA-based programs target neurological diseases at this point (reviewed in Brites, 2020 ; Reza-Zaldivar et al, 2020 ; Innao et al, 2020 ; Table 2 and Figure 2 ; miRagen, 2020 ; Regulus, 2020 ).…”

Section: Novel Biological Mechanisms Accessible Through Nucleic Acid–based Therapeuticsmentioning

confidence: 99%

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

Khorkova

Hsiao

Wahlestedt

2021

Front. Mol. Biosci.

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The possibility of rational design and the resulting faster and more cost-efficient development cycles of nucleic acid–based therapeutics (NBTs), such as antisense oligonucleotides, siRNAs, and gene therapy vectors, have fueled increased activity in developing therapies for orphan diseases. Despite the difficulty of delivering NBTs beyond the blood–brain barrier, neurological diseases are significantly represented among the first targets for NBTs. As orphan disease NBTs are now entering the clinical stage, substantial efforts are required to develop the scientific background and infrastructure for NBT design and mechanistic studies, genetic testing, understanding natural history of orphan disorders, data sharing, NBT manufacturing, and regulatory support. The outcomes of these efforts will also benefit patients with “common” diseases by improving diagnostics, developing the widely applicable NBT technology platforms, and promoting deeper understanding of biological mechanisms that underlie disease pathogenesis. Furthermore, with successes in genetic research, a growing proportion of “common” disease cases can now be attributed to mutations in particular genes, essentially extending the orphan disease field. Together, the developments occurring in orphan diseases are building the foundation for the future of personalized medicine. In this review, we will focus on recent achievements in developing therapies for orphan neurological disorders.

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“…Because brain cells can release EXs and EMVs which can pass from the brain and CNS into the blood, brain-derived vesicles isolated from the systemic circulation may be of use to monitor diseases operating in the CNS, thus improving clinical diagnoses and prognoses (Barbagallo et al, 2020 [ 46 ]). This may also be of use in analyzing the efficacy of pharmaceuticals and/or therapeutic interventions being used to intervene in the AD process via the analysis of EXs and EMVs in blood plasma (Cha et al, 2019 [ 65 ]; Barbagallo et al, 2020 [ 46 ]).…”

Section: Selective Micrornas In Exs and Emvsmentioning

confidence: 99%

Vesicular Transport of Encapsulated microRNA between Glial and Neuronal Cells

Lukiw

Pogue²

2020

IJMS

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Exosomes (EXs) and extracellular microvesicles (EMVs) represent a diverse assortment of plasma membrane-derived nanovesicles, 30–1000 nm in diameter, released by all cell lineages of the central nervous system (CNS). They are examples of a very active and dynamic form of extracellular communication and the conveyance of biological information transfer essential to maintain homeostatic neurological functions and contain complex molecular cargoes representative of the cytoplasm of their cells of origin. These molecular cargoes include various mixtures of proteins, lipids, proteolipids, cytokines, chemokines, carbohydrates, microRNAs (miRNA) and messenger RNAs (mRNA) and other components, including end-stage neurotoxic and pathogenic metabolic products, such as amyloid beta (Aβ) peptides. Brain microglia, for example, respond to both acute CNS injuries and degenerative diseases with complex reactions via the induction of a pro-inflammatory phenotype, and secrete EXs and EMVs enriched in selective pathogenic microRNAs (miRNAs) such as miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155, and others that are known to promote neuro-inflammation, induce complement activation, disrupt innate–immune signaling and deregulate the expression of neuron-specific phosphoproteins involved in neurotropism and synaptic signaling. This communication will review our current understanding of the trafficking of miRNA-containing EXs and EMVs from astrocytes and “activated pro-inflammatory” microglia to target neurons in neurodegenerative diseases with an emphasis on Alzheimer’s disease wherever possible.

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Regulatory function of microRNAs in microglia

Cited by 46 publications

References 135 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

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

Vesicular Transport of Encapsulated microRNA between Glial and Neuronal Cells

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