miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons

Roser, Anna-Elisa; Gomes, Lucas Caldi; Halder, Rashi; Jain, Gaurav; Maass, Fabian; Tönges, Lars; Tatenhorst, Lars; Bähr, Mathias; Fischer, André; Lingor, Paul

doi:10.1016/j.omtn.2018.01.005

Cited by 38 publications

(32 citation statements)

References 52 publications

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“…While Pitx3 upregulates miR-133b precursor expression by binding to the promoter region of miR-133b, the 3'-untranslated region (3'-UTR) of Pitx3 is targeted by miR-133b activity. 55 Overall, these reports suggest that there are ongoing interactions between Pitx3, Nurr1, and GDNF, on one hand, and miRNA molecules, on the other hand, that shape the DAergic fate of target cells under differentiation. 39 One such suppressing miRNA molecule, miR-383, inhibits GDNF protein translation and its suppression enhances GDNF expression leading to improved therapeutic potential of mesenchymal stem cells.…”

Section: Underlying Molecular Mechanismsmentioning

confidence: 96%

Complementation of dopaminergic signaling by Pitx3–GDNF synergy induces dopamine secretion by multipotent Ntera2 cells

Boroujeni

Aliaghaei

Maghsoudi

et al. 2019

J of Cellular Biochemistry

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Human teratocarcinoma cell line Ntera2 (NT2) expresses dopamine signals and has shown its safe profile for clinical applications. Attempts to restore complete dopaminergic (DAergic) phenotype enabling these cells to secrete dopamine have not been fully successful so far. We applied a blend of gene transfer techniques and a defined medium to convert NT2 cells to fully DAergic. The cells were primarily engineered to overexpress the Pitx3 gene product and then cultured in a growth medium supplemented with knockout serum and retinoic acid to form embroid bodies (EBs). Trypsinization of EB colonies produced single cells ready for differentiation. Neuronal/DAergic induction was promoted by applying conditioned medium taken from engineered human astrocytomas over‐secreting glial cell‐derived neurotrophic factor (GDNF). Immunocytochemistry, reverse‐transcription and real‐time polymerase chain reaction analyses confirmed significantly induced expression of molecules involved in dopamine signaling and metabolism including tyrosine hydroxylase, Nurr1, dopamine transporter, and aromatic acid decarboxylase. High‐performance liquid chromatography analysis indicated release of dopamine only from a class of fully differentiated cells expressing Pitx3 and exposed to GDNF. In addition, Pitx3 and GDNF additively promoted in vitro neuroprotection against Parkinsonian toxin. One month after transplantation to the striatum of 6‐OHDA‐leasioned rats, differentiated NT2 cells survived and induced significant increase in striatal volume. Besides, cell implantation improved motor coordination in Parkinson's disease (PD) rat models. Our findings highlight the importance of Pitx3–GDNF interplay in dopamine signaling and indicate that our strategy might be useful for the restoration of DAergic fate of NT2 cells to make them clinically applicable toward cell replacement therapy of PD.

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Section: Underlying Molecular Mechanismsmentioning

confidence: 96%

Complementation of dopaminergic signaling by Pitx3–GDNF synergy induces dopamine secretion by multipotent Ntera2 cells

Boroujeni

Aliaghaei

Maghsoudi

et al. 2019

J of Cellular Biochemistry

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“…Interestingly, various microRNAs possess a therapeutic potential and provide neuroprotection against neuroinflammation by targeting PD-associated genes ( Table 1 ). In 2018, Roser et al, reported the neuroprotective role of miR-182-5p and miR-183-5p, which downregulated GDNF (glial cell-derived neurotrophic factor) and protected DA neurons against neuronal damage in the PD model [ 49 ]. A cytoplasmic protein NLRP3 belongs to an inflammatory signaling complex, inflammasome, plays a significant role in inflammation-mediated pyrophosphorylation neurodegeneration of DA in substantia nigra par compacta (SNpc) in PD [ 55 , 56 , 57 ].…”

Section: Epigenetics and Neuroinflammation In Pdmentioning

confidence: 99%

Epigenetic Regulation of Neuroinflammation in Parkinson’s Disease

Rasheed

Liang

Wang

et al. 2021

IJMS

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Neuroinflammation is one of the most significant factors involved in the initiation and progression of Parkinson’s disease. PD is a neurodegenerative disorder with a motor disability linked with various complex and diversified risk factors. These factors trigger myriads of cellular and molecular processes, such as misfolding defective proteins, oxidative stress, mitochondrial dysfunction, and neurotoxic substances that induce selective neurodegeneration of dopamine neurons. This neuronal damage activates the neuronal immune system, including glial cells and inflammatory cytokines, to trigger neuroinflammation. The transition of acute to chronic neuroinflammation enhances the susceptibility of inflammation-induced dopaminergic neuron damage, forming a vicious cycle and prompting an individual to PD development. Epigenetic mechanisms recently have been at the forefront of the regulation of neuroinflammatory factors in PD, proposing a new dawn for breaking this vicious cycle. This review examined the core epigenetic mechanisms involved in the activation and phenotypic transformation of glial cells mediated neuroinflammation in PD. We found that epigenetic mechanisms do not work independently, despite being coordinated with each other to activate neuroinflammatory pathways. In this regard, we attempted to find the synergic correlation and contribution of these epigenetic modifications with various neuroinflammatory pathways to broaden the canvas of underlying pathological mechanisms involved in PD development. Moreover, this study highlighted the dual characteristics (neuroprotective/neurotoxic) of these epigenetic marks, which may counteract PD pathogenesis and make them potential candidates for devising future PD diagnosis and treatment.

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“…Levels of miR-148a-3p were associated with glycemic status and glucose levels [ 111 ]. miR-182-5p mediates nigrostriatal protection in the MPTP model of PD [ 137 ]. miR-182-5p was very highly expressed in individuals with prediabetes or type 2 DM, and miR-182-5p was observed to be significantly under-expressed in type 2 DM relative to prediabetes [ 140 ].…”

Section: Microrna Biomarkersmentioning

confidence: 99%

MicroRNAs, Parkinson’s Disease, and Diabetes Mellitus

Wang

2021

IJMS

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Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the population over the age of 60. Diabetes Mellitus (DM) is a metabolic disorder that affects approximately 25% of adults over the age of 60. Recent studies showed that DM increases the risk of developing PD. The link between DM and PD has been discussed in the literature in relation to different mechanisms including mitochondrial dysfunction, oxidative stress, and protein aggregation. In this paper, we review the common microRNA (miRNA) biomarkers of both diseases. miRNAs play an important role in cell differentiation, development, the regulation of the cell cycle, and apoptosis. They are also involved in the pathology of many diseases. miRNAs can mediate the insulin pathway and glucose absorption. miRNAs can also regulate PD-related genes. Therefore, exploring the common miRNA biomarkers of both PD and DM can shed a light on how these two diseases are correlated, and targeting miRNAs is a potential therapeutic opportunity for both diseases.

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miR-182-5p and miR-183-5p Act as GDNF Mimics in Dopaminergic Midbrain Neurons

Cited by 38 publications

References 52 publications

Complementation of dopaminergic signaling by Pitx3–GDNF synergy induces dopamine secretion by multipotent Ntera2 cells

Complementation of dopaminergic signaling by Pitx3–GDNF synergy induces dopamine secretion by multipotent Ntera2 cells

Epigenetic Regulation of Neuroinflammation in Parkinson’s Disease

MicroRNAs, Parkinson’s Disease, and Diabetes Mellitus

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