Overexpression of α-Synuclein Down-Regulates BDNF Expression
Key Laboratory of Bioactive Substances and Resources Utilization, Ministry of Education, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People's Republic of China. Cellular and Molecular Neurobiology
(Impact Factor: 2.51).
08/2010; 30(6):939-46. DOI: 10.1007/s10571-010-9523-y
Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by the selective loss of nigrostriatal dopaminergic neurons. However, the molecular pathways leading to the dopaminergic neuron degeneration have remained obscure until recently. Reports demonstrated that reduction of brain-derived neurotrophic factor (BDNF) was involved in the etiology and pathogenesis of PD, but its mechanism has not been elucidated. alpha-Synuclein has a causal role in Parkinson's disease, and could interfere with transcriptional regulation of dopamine neurons. In this study, alpha-synuclein overexpression was found to decrease the expression of BDNF, and also to suppress the transactivation of nuclear factors of activated T-cells (NFAT) and cAMP response element binding protein (CREB), both of which regulate BDNF expression. Furthermore, overexpressed alpha-synuclein could associate with protein kinase C (PKC) and impair its activity. Meanwhile glycogen synthase kinase-3beta (GSK3beta) was activated and extracellular signal-regulated protein kinase (ERK) activity was inhibited by overexpression of alpha-synuclein; both of them were downstream kinases of PKC. Therefore, the impaired PKC signal pathway caused by alpha-synuclein overexpression might account at least partially for the down-regulation of BDNF.
Available from: Epaminondas Doxakis
- "Previous work from our group has shown that mir-7 and mir-153 significantly regulate the expression of α-synuclein, a protein encoded by the gene SNCA that belongs to the PARK gene family (Doxakis, 2010). A-synuclein plays a seminal role in neurodegeneration and has been shown, among others, to affect signaling by modulating neurotrophin BDNF expression and AKT activity (Yuan et al., 2010; Chung et al., 2011). Based on the intrinsic property of miRs to regulate the expression of multiple proteins and possibly the activation of signaling cascades, in the present study we wished to investigate if miR-7 and miR-153 protect neurons exposed to PD insults via altering intracellular signaling. "
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ABSTRACT: Differential expression of microRNAs (miRs) in the brain of patients with neurodegenerative diseases suggests that they may have key regulatory roles in the development of these disorders. Two such miRs, miR-7, and miR-153 have recently been shown to target α-synuclein, a protein critically involved in the pathological process of Parkinson's disease. By using a well-established in culture Parkinson's disease model that of neurotoxin 1-Methyl-4-Phenyl-Pyridinium (MPP(+)), we examined whether miR-7 and miR-153 display neuroprotective properties. Herein, we demonstrate that treatment of cortical neurons with MPP(+) induced a dose-dependent cell death with apoptotic characteristics. This was reflected in altered intracellular signaling characterized by increased levels of activated kinases p38MAPK and ERK1/2 and reduced levels of activated AKT, p70S6K, and SAPK/JNK. Overexpression of miR-7 or miR-153 by adenoviral transduction protected cortical neurons from MPP(+)-induced toxicity, restored neuronal viability and anti-apoptotic BCL-2 protein levels while attenuated activation of caspase-3. Moreover, both miR-7 and miR-153 interfered with MPP(+)-induced alterations in intracellular signaling pathways in a partially overlapping manner; specifically, they preserved activation of mTOR and SAPK/JNK signaling pathways in the MPP(+)-treated neurons, while miR-153 also attenuated MPP(+)-induced activation of p38MAPK. No major effects were observed in the rest of signaling cascades or proteins investigated. Furthermore, the neuroprotective effect of miR-7 and miR-153 was alleviated when MPP(+) was co-administered with rapamycin. Taken together, our results suggest that miR-7 and miR-153 protect neurons from cell death by interfering with the MPP(+)-induced downregulation of mTOR signaling.
Frontiers in Cellular Neuroscience 07/2014; 8:182. DOI:10.3389/fncel.2014.00182 · 4.29 Impact Factor
Available from: PubMed Central
- "Evidence has been reported of activated T cells in the substantia nigra in rodent PD models (Kurkowska-Jastrzebska et al., 1999) and postmortem PD brains (Brochard et al., 2009), and elimination of T cells attenuated dopaminergic neuron loss in rodent PD models (Brochard et al., 2009). As in AD, there is evidence both that GSK3 contributes to neuronal degenerative processes in PD (King et al., 2001; Chen et al., 2004) and that neurotoxic mechanisms, such as α-synuclein in PD, activate GSK3 (Duka et al., 2009; Yuan et al., 2010). Thus, inhibition of GSK3 may protect susceptible neurons from degeneration and reduce the inflammation that appears to promote neurodegenerative processes in PD. "
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ABSTRACT: Elevated markers of neuroinflammation have been found to be associated with many psychiatric and neurodegenerative diseases, such as mood disorders, Alzheimer's disease, and multiple sclerosis (MS). Since neuroinflammation is thought to contribute to the pathophysiology of these diseases and to impair responses to therapeutic interventions and recovery, it is important to identify mechanisms that regulate neuroinflammation and potential targets for controlling neuroinflammation. Recent findings have demonstrated that glycogen synthase kinase-3 (GSK3) is an important regulator of both the innate and adaptive immune systems' contributions to inflammation. Studies of the innate immune system have shown that inhibitors of GSK3 profoundly alter the repertoire of cytokines that are produced both by peripheral and central cells, reducing pro-inflammatory cytokines, and increasing anti-inflammatory cytokines. Furthermore, inhibitors of GSK3 promote tolerance to inflammatory stimuli, reducing inflammatory cytokine production upon repeated exposure. Studies of the adaptive immune system have shown that GSK3 regulates the production of cytokines by T cells and the differentiation of T cells to subtypes, particularly Th17 cells. Regulation of transcription factors by GSK3 appears to play a prominent role in its regulation of immune responses, including of NF-κB, cyclic AMP response element binding protein, and signal transducer and activator of transcription-3. Invivo studies have shown that GSK3 inhibitors ameliorate clinical symptoms of both peripheral and central inflammatory diseases, particularly experimental autoimmune encephalomyelitis, the animal model of MS. Therefore, the development and application of GSK3 inhibitors may provide a new therapeutic strategy to reduce neuroinflammation associated with many central nervous system diseases.
Frontiers in Molecular Neuroscience 08/2011; 4:18. DOI:10.3389/fnmol.2011.00018 · 4.08 Impact Factor
Available from: Natalia P Bondar
- "Differently directed changes BDNF and α-Syn were revealed in the pathogenesis of Parkinson's disease affecting dopaminergic systems ; . Moreover there was indication that overexpression of α-syn may decrease BDNF expression . It was supposed that Bdnf gene together with Snca gene in the VTA and raphe nuclei of midbrain may be involved in the consequences of repeated agonistic interactions. "
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ABSTRACT: Alpha-synuclein (α-Syn) is a small neuronal protein that has been found to be expressed throughout the brain. It has been shown that α-Syn regulates the homeostasis of monoamine neurotransmitters and is involved in various degenerative and affective disorders. There is indication that α-Syn may regulate expression of the brain-derived neurotropic factor (BDNF) which plays an important role in the mood disorders.
The study aimed to analyze the mRNA levels of Snca and Bdnf genes in the ventral tegmental area (VTA) and raphe nuclei of the midbrain in male mice that had each won or defeated 20 encounters (20-time winners and 20-time losers, respectively) in daily agonistic interactions. Groups of animals that had the same winning and losing track record followed by a no-fight period for 14 days (no-fighting winners and no-fighting losers) were also studied. Snca mRNA levels were increased in the raphe nuclei in the 20-time losers and in the VTA of the 20-time winners. After no-fight period Snca mRNA levels decreased in both groups. Snca mRNA levels were similar to the control level in the VTA of the 20-time losers and in the raphe nuclei of the 20-time winners. However Snca gene expression increased in these areas in the no-fighting winners and no-fighting losers in comparison with respective mRNA levels in animals before no-fight period. Bdnf mRNA levels increased in VTA of 20-time winners. Significant positive correlations were found between the mRNA levels of Snca and Bdnf genes in the raphe nuclei.
Social experience affects Snca gene expression depending on brain areas and functional activity of monoaminergic systems in chronically victorious or defeated mice. These findings may be useful for understanding the mechanisms of forming different alpha-synucleinopathies.
PLoS ONE 11/2010; 5(11):e14089. DOI:10.1371/journal.pone.0014089 · 3.23 Impact Factor
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