Dataset Information

MiR-34a/BCL-2 signaling axis contributes to apoptosis in MPP⁺ -induced SH-SY5Y cells.

ABSTRACT:

Background

Parkinson's disease (PD) is a neurodegenerative disorder which mainly affects the elderly population of various societies. The main hallmark of this disease is the loss of dopaminergic (DA) neurons. So far, numerous studies have implied the role of microRNAs in fine-tuning cellular processes including apoptosis. Studies have also shown that miR-34a is mainly involved in age-related disorders including Alzheimer's disease, and its expression is usually higher in the brain sample patients. Furthermore, the key role of miR-34a in the expression of BCL-2, and thus, in vitro and in vivo apoptosis has been revealed. miR-34a/BCL-2 axis is therefore of critical importance in inducing or inhibiting apoptosis.

Methods

In this study, human SH-SY5Y cells were treated with MPP+ and the expression of miR-34a and BCL2 was assessed.

Results

Our results also showed that treating human SH-SY5Y neuronal cells using MPP⁺ to induce oxidative stress and apoptosis led to the upregulation of miR-34a, as compared to the nontreated control group. Moreover, evaluating the expression level of BCL-2 in these cells indicated a contradictory pattern, as compared with miR-34a. It was also revealed that the expression of BCL-2 was significantly decreased in MPP⁺ -treated cells, thereby confirming previous studies regarding a new concept. In this study, we show that miR-34a/BCL-2 axis is directly correlated with oxidative stress and apoptosis in SH-SY5Y cells as a model of DA neurons.

Conclusion

miR-34a and its target gene, BCL-2, play a possible role in the induction of apoptosis in DA neurons, and therefore, they have a potential role in the pathogenesis of PD. Consequently, the therapeutic potential of miR-34a could be considered in order to inhibit the progression of PD.

SUBMITTER: Shanesazzade Z

PROVIDER: S-EPMC6305653 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Publications

miR-34a/BCL-2 signaling axis contributes to apoptosis in MPP<sup>+</sup> -induced SH-SY5Y cells.

Shanesazzade Zahra Z Peymani Maryam M Ghaedi Kamran K Nasr Esfahani Mohammad Hossein MH

Molecular genetics & genomic medicine 20180916 6

<h4>Background</h4>Parkinson's disease (PD) is a neurodegenerative disorder which mainly affects the elderly population of various societies. The main hallmark of this disease is the loss of dopaminergic (DA) neurons. So far, numerous studies have implied the role of microRNAs in fine-tuning cellular processes including apoptosis. Studies have also shown that miR-34a is mainly involved in age-related disorders including Alzheimer's disease, and its expression is usually higher in the brain sampl ...[more]

PMID: 30221494

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Project description:Complex pathophysiology of Parkinson's disease involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in Parkinson's disease and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. To unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes, respectively, and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP(+) and rotenone. SNJ-1945, a cell-permeable calpain inhibitor was tested for its neuroprotective efficacy. MPP(+) and rotenone dose-dependently elevated the levels of intracellular free Ca(2+) and induced a concomitant rise in the levels of active calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP(+) and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators cyclooxygenase-2 (Cox-2 and cleaved p10 fragment of caspase-1) were up-regulated in the cholinergic phenotype, which could be dose-dependently attenuated by the calpain inhibitor. Overall, SNJ-1945 was efficacious against MPP(+) or rotenone-induced reactive oxygen species generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with calpain inhibitor administration 1-3 h after exposure to MPP(+) or rotenone. Taken together, these results indicate that calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious calpain inhibitor in this context. SH-SY5Y cells, differentiated as dopaminergic (TH positive) and cholinergic (ChAT positive), were used as in vitro models for Parkinson's disease. MPP+ and rotenone induced up-regulation of calpain, expression, and activity as a common mechanism of neurodegeneration. SNJ-1945, a novel calpain inhibitor, protected both the cell phenotypes against MPP+ and rotenone.

Project description:Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) were examined in SH-SY5Y cells. FCPR16 (12.5-50??M) dose-dependently reduced MPP+-induced loss of cell viability, accompanied by reductions in nuclear condensation and lactate dehydrogenase release. The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells. Furthermore, FCPR16 (25??M) significantly suppressed the accumulation of reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential (??m) and attenuated the expression of malonaldehyde level. Further studies disclosed that FCPR16 enhanced the levels of cAMP and the exchange protein directly activated by cAMP (Epac) in SH-SY5Y cells. Western blotting analysis revealed that FCPR16 increased the phosphorylation of cAMP response element-binding protein (CREB) and protein kinase B (Akt) down-regulated by MPP+ in SH-SY5Y cells. Moreover, the inhibitory effects of FCPR16 on the production of ROS and ??m loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401. Collectively, these results suggest that FCPR16 attenuates MPP+-induced dopaminergic degeneration via lowering ROS and preventing the loss of ??m in SH-SY5Y cells. Mechanistically, cAMP/PKA/CREB and Epac/Akt signaling pathways are involved in these processes. Our findings indicate that FCPR16 is a promising pre-clinical candidate for the treatment of PD and possibly other oxidative stress-related neuronal diseases.

Dataset Information

MiR-34a/BCL-2 signaling axis contributes to apoptosis in MPP⁺ -induced SH-SY5Y cells.

Background

Methods

Results

Conclusion

Publications

miR-34a/BCL-2 signaling axis contributes to apoptosis in MPP<sup>+</sup> -induced SH-SY5Y cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

MiR-34a/BCL-2 signaling axis contributes to apoptosis in MPP+ -induced SH-SY5Y cells.

Background

Methods

Results

Conclusion

Publications

miR-34a/BCL-2 signaling axis contributes to apoptosis in MPP<sup>+</sup> -induced SH-SY5Y cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

MiR-34a/BCL-2 signaling axis contributes to apoptosis in MPP⁺ -induced SH-SY5Y cells.