Elevated exosomal secretion of miR-124-3p from spinal neurons positively associates with disease severity in ALS

Yelick, Julia; Men, Yuqin; Jin, Shijie; Seo, Sabrina; Espejo-Porras, Francisco; Yang, Yongjie

doi:10.1016/j.expneurol.2020.113414

Cited by 47 publications

(52 citation statements)

References 49 publications

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“…We and other authors have found an elevation of miR-124 expression levels in ALS models and patients [ 3 , 21 , 22 , 23 , 24 , 25 ]. Our prior data revealed an increased expression of this miRNA in mSOD1 MN-like cells [ 25 ] and in the SC of symptomatic mSOD1 mice [ 3 ].…”

Section: Discussionmentioning

confidence: 53%

“…Despite the critical role of miR-124 in neuronal differentiation and neurite outgrowth [ 30 ], its increased levels were associated with pathological events in neurodegenerative diseases, including ALS [ 24 , 31 ]. We have previously demonstrated that miR-124 is upregulated in NSC-34 mSOD1 MNs [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

“…In the case of miR-124, its increased levels were associated to MN proneness to early apoptosis and MN dysfunction in ALS, though it may also compromise neuro-immune homeostatic balance. Recently, upregulation of miR-124 in exosomes from spinal MNs and in CSF from ALS patients was proposed as a potential biomarker based on its correlation with disease severity [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of miR-124 and miR-125b was found in the brain of ALS mice at late disease stages, where the first was associated with neural activity and the later with corticospinal tract degeneration [ 21 ]. Their elevation in the CSF of ALS patients was linked to neuronal demise and neuroinflammation/gliosis, respectively, as well as with disease severity, suggesting miR-124 upregulation as a potential biomarker [ 22 , 23 , 24 ]. Our studies in the SC of mSOD1 mice demonstrated that miR-124 and miR-146a only increased in the symptomatic phase, while miR-155 upregulation was observed in early stages [ 3 ], reinforcing the relevance of neuroinflammation in the disease.…”

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: Discussionmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Huntington's disease Alzheimer's disease Parkinson's disease Amyotrophic lateral sclerosis "Non-specific" exosomes Absence of mHTT (Denis et al, 2018) Phosphorylated tau (Saman et al, 2012) ↓REST (Goetzl et al, 2015) ↑miR195 and miR24 ↓miR19b (Cao et al, 2017) Altered levels of miRNA (Yelick et al, 2020) NDEs ↑Aβ1-42 ↓Synaptic proteins ↑TDP43 (Fiandaca et al, 2015;Goetzl et al, 2016Goetzl et al, , 2018Zhang et al, 2020) ↓synaptophysin, synaptotagmin and SNAP-25 (Goetzl et al, 2016;Agliardi et al, 2019) ↓miR132 and miR-212 (Walsh et al, 2019) ↑DJ1 and α-synuclein (Zhao et al, 2019) ↑α-synuclein and clusterin (Jiang et al, 2020) ↑α-synuclein (Shi et al, 2014;Jiang et al, 2020;Fu et al, 2020;Niu et al, 2020) Altered levels of miRNA (Katsu et al, 2019;Banack et al, 2020) NDEs, neuronally derived exosomes; mHTT, mutant huntingtin; REST, repressor element 1-silencing transcription factor; Aβ1-42, amyloid beta-42; TDP43, TAR DNAbinding protein 43; SNAP-25, 25 kD synaptosomal protein; miR, micro RNA.…”

Section: Exosome Sourcementioning

confidence: 99%

Exosomes: Innocent Bystanders or Critical Culprits in Neurodegenerative Diseases

Beatriz

Vilaça

Lopes

2021

Front. Cell Dev. Biol.

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Extracellular vesicles (EVs) are nano-sized membrane-enclosed particles released by cells that participate in intercellular communication through the transfer of biologic material. EVs include exosomes that are small vesicles that were initially associated with the disposal of cellular garbage; however, recent findings point toward a function as natural carriers of a wide variety of genetic material and proteins. Indeed, exosomes are vesicle mediators of intercellular communication and maintenance of cellular homeostasis. The role of exosomes in health and age-associated diseases is far from being understood, but recent evidence implicates exosomes as causative players in the spread of neurodegenerative diseases. Cells from the central nervous system (CNS) use exosomes as a strategy not only to eliminate membranes, toxic proteins, and RNA species but also to mediate short and long cell-to-cell communication as carriers of important messengers and signals. The accumulation of protein aggregates is a common pathological hallmark in many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. Protein aggregates can be removed and delivered to degradation by the endo-lysosomal pathway or can be incorporated in multivesicular bodies (MVBs) that are further released to the extracellular space as exosomes. Because exosome transport damaged cellular material, this eventually contributes to the spread of pathological misfolded proteins within the brain, thus promoting the neurodegeneration process. In this review, we focus on the role of exosomes in CNS homeostasis, their possible contribution to the development of neurodegenerative diseases, the usefulness of exosome cargo as biomarkers of disease, and the potential benefits of plasma circulating CNS-derived exosomes.

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Exosomes in brain diseases: Pathogenesis and therapeutic targets

Pang

et al. 2023

MedComm

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Exosomes are extracellular vesicles with diameters of about 100 nm that are naturally secreted by cells into body fluids. They are derived from endosomes and are wrapped in lipid membranes. Exosomes are involved in intracellular metabolism and intercellular communication. They contain nucleic acids, proteins, lipids, and metabolites from the cell microenvironment and cytoplasm. The contents of exosomes can reflect their cells’ origin and allow the observation of tissue changes and cell states under disease conditions. Naturally derived exosomes have specific biomolecules that act as the “fingerprint” of the parent cells, and the contents changed under pathological conditions can be used as biomarkers for disease diagnosis. Exosomes have low immunogenicity, are small in size, and can cross the blood–brain barrier. These characteristics make exosomes unique as engineering carriers. They can incorporate therapeutic drugs and achieve targeted drug delivery. Exosomes as carriers for targeted disease therapy are still in their infancy, but exosome engineering provides a new perspective for cell‐free disease therapy. This review discussed exosomes and their relationship with the occurrence and treatment of some neuropsychiatric diseases. In addition, future applications of exosomes in the diagnosis and treatment of neuropsychiatric disorders were evaluated in this review.

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Elevated exosomal secretion of miR-124-3p from spinal neurons positively associates with disease severity in ALS

Cited by 47 publications

References 49 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

Exosomes: Innocent Bystanders or Critical Culprits in Neurodegenerative Diseases

Exosomes in brain diseases: Pathogenesis and therapeutic targets

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