Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

McMillan, Kirsty J; Murray, Tracey K.; Bengoa-Vergniory, Nora; Llana, Oscar Cordero; Cooper, Jane; Buckley, A; Wade‐Martins, Richard; Uney, James B.; O’Neill, Michael; Wong, Liang Fong; Caldwell, Maeve A.

doi:10.1016/j.ymthe.2017.08.017

Cited by 115 publications

(107 citation statements)

References 56 publications

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“…In agreement, the expression of miR-7 in different tissues during neuronal development is inversely related to the α-Syn content, suggesting that this miRNA exerts a tuning role on α-Syn levels [37]. While the loss of miR-7 function contributes to α-Syn accumulation-which can be reversed by a microRNA replacement, this target also provides additional effects by regulating other genes related to PD pathogenesis [34,36,86]. miR-7 protects cells against oxidative stress by downregulating VDAC1 and Keap1.…”

Section: Neuroprotective Mirna-based Approaches In Models Of Pdmentioning

confidence: 61%

“…MiR-7 well represents how an alteration in microRNA content directly affects a targeted mRNA. Patients with PD present reduced levels of miR-7 in brain regions related to disease neuropathology, especially the substantia nigra, and depletion of this miRNA is functionally related with α-Syn accumulation and the further neuron loss [36,86]. In addition to miR-7, miR-153 also recognizes sequences in 3 -UTR region of α-Syn, thereby operating additively to downregulate the gene.…”

Section: Mirnas and Alpha Synuclein (α-Syn) Accumulationmentioning

confidence: 99%

“…A significant decrease in miR-7 was found in the substantia nigra of patients with PD, and, therefore, this change was proposed to play a role in α-Syn accumulation [86]. The neuroprotective actions of miR-7 were first studied in cellular models of PD, which evidenced the ability of this miRNA to target and down-regulate α-Syn by binding to its 3'-UTR mRNA region [36,37].…”

Section: Neuroprotective Mirna-based Approaches In Models Of Pdmentioning

confidence: 99%

See 2 more Smart Citations

The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease

Titze‐de‐Almeida

Soto-Sánchez

Fernández

et al. 2020

Cells

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MicroRNAs (miRNAs) are small double-stranded RNAs that exert a fine-tuning sequence-specific regulation of cell transcriptome. While one unique miRNA regulates hundreds of mRNAs, each mRNA molecule is commonly regulated by various miRNAs that bind to complementary sequences at 3’-untranslated regions for triggering the mechanism of RNA interference. Unfortunately, dysregulated miRNAs play critical roles in many disorders, including Parkinson’s disease (PD), the second most prevalent neurodegenerative disease in the world. Treatment of this slowly, progressive, and yet incurable pathology challenges neurologists. In addition to L-DOPA that restores dopaminergic transmission and ameliorate motor signs (i.e., bradykinesia, rigidity, tremors), patients commonly receive medication for mood disorders and autonomic dysfunctions. However, the effectiveness of L-DOPA declines over time, and the L-DOPA-induced dyskinesias commonly appear and become highly disabling. The discovery of more effective therapies capable of slowing disease progression –a neuroprotective agent–remains a critical need in PD. The present review focus on miRNAs as promising drug targets for PD, examining their role in underlying mechanisms of the disease, the strategies for controlling aberrant expressions, and, finally, the current technologies for translating these small molecules from bench to clinics.

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Section: Neuroprotective Mirna-based Approaches In Models Of Pdmentioning

confidence: 61%

Section: Mirnas and Alpha Synuclein (α-Syn) Accumulationmentioning

confidence: 99%

Section: Neuroprotective Mirna-based Approaches In Models Of Pdmentioning

confidence: 99%

See 1 more Smart Citation

The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease

Titze‐de‐Almeida

Soto-Sánchez

Fernández

et al. 2020

Cells

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show abstract

“…For instance, miR-7 is a tumor suppressor and increase cisplatin sensitivity of gastric cancer cells by targeting mTOR, indicating its potential application for the treatment of human gastric cancer in the future [48]. Moreover, miR-7 can regulate α-synuclein expression and downregulation of miR-7 results in the loss of dopaminergic neuronal in the substantia nigra [49]. In our previous study, miR-7 can regulate the pathology of acute lung injury [23].…”

Section: Discussionmentioning

confidence: 94%

MicroRNA-7, synergizes with RORα, negatively controls the pathology of brain tissue inflammation

Yue

Zhao

Chen

et al. 2020

J Neuroinflammation

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Background: Accumulating evidence has documented that microRNA-7 (miR-7) plays an important role in the pathology of various diseases. However, the potential role of miR-7 in brain tissue inflammation (BTI) remains unclear. Methods: We detected the expression of miR-7 in LPS-induced murine BTI model and observed the possible effects of miR-7 deficiency on the pathology of BTI. To elucidate the mechanism, the target gene of miR-7 was screened out by Gene chip assay and its potential roles in BTI were evaluated by Western blot, immunofluorescence, and RNAi assay, respectively.Results: MiR-7 was upregulated in brain tissue in BTI mice and its deficiency could significantly aggravate the pathology of brain tissue. Moreover, RORα, a new target molecule of miR-7, was upregulated in brain tissue from miR-7 deficiency BTI mice. Of note, downregulation of RORα could remarkably exacerbate the pathology of brain tissue and elevate the transduction of NF-κB and ERK1/2 signaling pathways in brain tissue from miR-7 deficiency BTI mice. Furthermore, RORα and miR-7 were dominantly co-expressed in neurons of BTI mice. Finally, RORα synergized with miR-7 to control the inflammatory reaction of neuronal cells in response to LPS stimulation.Conclusions: MiR-7 expression is upregulated in BTI model. Moreover, miR-7 synergizes with its target gene RORα to control the inflammation reaction of neurons, thereby orchestrating the pathology of BTI.

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“…This holds particular importance for SNCA as different isoforms and expression levels are predicted to affect SNCA aggregation (Bungeroth et al., ; Manda, Yedlapudi, Korukonda, Bojja, & Kalivendi, ). Moreover, the 3′UTR harbors several miR sites, targeted by multiple miRs including miR7 and miR34b,c, shown to affect alpha‐synuclein expression and related phenotypes (Junn et al., ; Kabaria, Choi, Chaudhuri, Mouradian, & Junn, ; McMillan et al., ; Tatura et al., ). Association studies alone have failed to definitively identify all key functional variant(s), because of large haplotype blocks across the gene harboring multiple candidate variants, and significant linkage disequilibrium (LD) in the 3′UTR.…”

Section: Introductionmentioning

confidence: 99%

Alpha‐synuclein mRNA isoform formation and translation affected by polymorphism in the human SNCA 3ʹUTR

Barrie

Lee

Frater

et al. 2018

Molec Gen & Gen Med

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BackgroundMultiple variants in SNCA, encoding alpha‐synuclein, a main component of Lewy bodies, are implicated in Parkinson's disease.MethodsWe searched for cis‐acting SNCA variants using allelic mRNA ratios in human brain tissues. In a SNCA 3′UTR (2,520 bp) luciferase reporter gene assay, translation in SH‐SY5Y cells in the presence of the rs17016074 G/A alleles was measured. To assess clinical impact, we queried neurocognitive genome‐wide association studies.ResultsAllelic ratios deviated up to twofold, measured at a marker SNP in the middle of a long 3′ untranslated region (3′UTR), but not at a marker at its start, suggesting regulation of 3′UTR processing. 3′UTR SNP rs17016074 G/A, minor allele frequency (MAF) <1% in Caucasians, 13% in Africans, strongly associates with large allelic mRNA expression imbalance (AEI), resulting in reduced expression of long 3′UTR isoforms. A second 3′UTR SNP (rs356165) associates with moderate AEI and enhances SNCA mRNA expression. The rs17016074 A allele reduces overall 3′UTR expression in luciferase reporter gene assays but supports more efficient translation, resolving previous contradictory results. We failed to detect significant genome‐wide associations for rs17016074, possibly a result of low MAF in Caucasians or its absence from most genotyping panels. In the “Genome Wide Association Study of Yoruba in Nigeria,” rs356165 was associated with reduced memory performance.ConclusionsHere, we identify two cis‐acting regulatory variants affecting SNCA mRNA expression, measured by allelic ratios in the 3′UTR. The rs17016074 minor A allele is associated with higher expression of luciferase protein activity. Resolving the genetic influence of SNCA polymorphisms requires study of the interactions between multiple regulatory variants with distinct frequencies among populations.

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Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

Cited by 115 publications

References 56 publications

The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease

The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease

MicroRNA-7, synergizes with RORα, negatively controls the pathology of brain tissue inflammation

Alpha‐synuclein mRNA isoform formation and translation affected by polymorphism in the human SNCA 3ʹUTR

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