miR-7 Replacement Therapy in Parkinson’s Disease

Titze‐de‐Almeida, Ricardo; Titze‐de‐Almeida, Simoneide Souza

doi:10.2174/1566523218666180430121323

Cited by 72 publications

(50 citation statements)

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“…In fact, the miR-7-dependent negative regulation of diencephalic DA cells appears to occur in the proliferative areas of the Wnt-responsive regions of the zebrafish brain, where DA precursors form and differentiate. This raises interesting implications in the analysis of molecular mechanisms underlying PD development, offering new miRNAs/signaling pathways cross-talks specifically targetable for its treatment, in the framework of existing research strategies [54][55][56].…”

Section: Mir-7 Manipulation Affects the Balance Of Wnt/shh Signaling mentioning

confidence: 99%

miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation

Adusumilli

Facchinello

Teh

et al. 2020

Cells

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During the development of the central nervous system, the proliferation of neural progenitors and differentiation of neurons and glia are tightly regulated by different transcription factors and signaling cascades, such as the Wnt and Shh pathways. This process takes place in cooperation with several microRNAs, some of which evolutionarily conserved in vertebrates, from teleosts to mammals. We focused our attention on miR-7, as its role in the regulation of cell signaling during neural development is still unclear. Specifically, we used human stem cell cultures and whole zebrafish embryos to study, in vitro and in vivo, the role of miR-7 in the development of dopaminergic (DA) neurons, a cell type primarily affected in Parkinson's disease. We demonstrated that the zebrafish homologue of miR-7 (miR-7a) is expressed in the forebrain during the development of DA neurons. Moreover, we identified 143 target genes downregulated by miR-7, including the neural fate markers TCF4 and TCF12, as well as the Wnt pathway effector TCF7L2. We then demonstrated that miR-7 negatively regulates the proliferation of DA-progenitors by inhibiting Wnt/β-catenin signaling in zebrafish embryos. In parallel, miR-7 positively regulates Shh signaling, thus controlling the balance between oligodendroglial and DA neuronal cell fates. In summary, this study identifies a new molecular cross-talk between Wnt and Shh signaling pathways during the development of DA-neurons. Being mediated by a microRNA, this mechanism represents a promising target in cell differentiation therapies for Parkinson's disease.

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Section: Mir-7 Manipulation Affects the Balance Of Wnt/shh Signaling mentioning

confidence: 99%

miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation

Adusumilli

Facchinello

Teh

et al. 2020

Cells

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“…For example, patients with PD and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced animals exhibit a significant decrease in the levels of miR-7 in brain tissue areas associated with dopaminergic neurodegeneration (17). Moreover, miR-7 has recently been shown to target α-synuclein, a protein involved in the pathological process of PD, and can therefore be used for the treatment of this disease (18).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR‑21 suppresses 1‑methyl‑4‑phenylpyridinium‑induced neuronal damage in MES23.5 cells

Mao

Ding

2019

Exp Ther Med

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Accumulating evidence suggests that overproduction of oxidative stress, increases neuroinflammation and activates apoptosis. These two processes are associated with the development of Parkinson's disease (PD). The present study aimed to investigate the role of miR-21 in the development of PD. 1-Methyl-4-phenylpyridinium (MPP + ) was used to induce a PD-like model in MES23.5 cells. The results of the reverse transcription-quantitative PCR assays indicated that miR-21 levels were markedly increased in MES23.5 cells following MPP + treatment. Furthermore, MES23.5 cells were transfected with miR-21 inhibitor, mimics and/ or relevant negative control, following MPP + administration. The results of the functional assays revealed that downregulation of miR-21 significantly attenuated the induction of cell apoptosis and reactive oxygen species (ROS) production, while it enhanced the survival of MPP + -induced MES23.5 cells. Furthermore, downregulation of miR-21 increased the expression levels of tyrosine hydroxylase, whereas suppression of miR-21 inhibited the production of pro-inflammatory cytokines [interleukin (IL)-6, IL-1β and tumor necrosis factor-α] in MES23.5 cells. Western blot analysis further indicated that the Bcl-2/Bax protein expression ratio was significantly increased and double luciferase assay analysis confirmed that Bcl-2 was a direct target of miR-21. Taken collectively, the data demonstrated that downregulation of miR-21 protected cells from MPP + -mediated cytotoxicity by the inhibition of apoptosis induction, the reduction of the inflammatory response and the suppression of ROS production. The present findings may provide novel approaches for PD clinical treatment.

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“…MicroRNAs are small RNA molecules that commonly originate from a 'canonical' pathway in which the biosynthesis begin in the cell nucleus and extend to the cytoplasm ( Figure 1) [33]. Two other sources of miRNAs exist; these molecules can be formed in cells from a 'noncanonical' pathway, and, in addition, they can be chemically synthesized for experimental assays as oligonucleotides that imitate the endogenous molecules, the miRNA mimics [33,34]. The Box 1 of Supplementary Material presents brief definitions of miRNA mimics and AntimiRs.…”

Section: Microrna Biogenesismentioning

confidence: 99%

“…AGO-Argonaute 2; CDS-Coding sequence region of mRNA; 3'-UTR-3' untranslated region; DGCR8-DiGeorge syndrome critical region gene 8; Dicer-a ribonuclease enzyme; Drosha-a ribonuclease enzyme; miRISC-RISC complex associated with a miRNA; Pol II-RNA polymerase II; pre-miRNA-miRNA precursor; pri-miRNA-primary miRNA; RISC-RNA-induced silencing complex; TRBP-HIV-1 Trans-activation response (TAR) RNA-binding protein. Reprinted with permission from Titze-de-Almeida and Titze-de-Almeida 2018, with modifications [34].…”

Section: Microrna Biogenesismentioning

confidence: 99%

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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miR-7 Replacement Therapy in Parkinson’s Disease

Cited by 72 publications

References 0 publications

miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation

miR-7 Controls the Dopaminergic/Oligodendroglial Fate through Wnt/β-catenin Signaling Regulation

Downregulation of miR‑21 suppresses 1‑methyl‑4‑phenylpyridinium‑induced neuronal damage in MES23.5 cells

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

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