Transcriptional regulation of the α-synuclein gene in human brain tissue

Brenner, Stephan; Wersinger, Christophe; Gasser, Thomas

doi:10.1016/j.neulet.2015.05.029

Cited by 21 publications

(26 citation statements)

References 23 publications

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“…In particular, regarding SNCA, a recent study has shown that overexpression of ZSCAN21 can both repress SNCA and increase SNCB expression in the SHSY5Y cell line. Moreover, another study (39) reported that ZSCAN21 binds directly to the intron 1 region of SNCA in human brain tissue. Therefore, given the important role of ZSCAN21 in the transcriptional regulation of SNCA in neuron-like cells, we aimed to investigate its role in the transcriptional regulation of SNCA in primary neuronal cultures and, most importantly, in vivo.…”

mentioning

confidence: 98%

Complex Effects of the ZSCAN21 Transcription Factor on Transcriptional Regulation of α-Synuclein in Primary Neuronal Cultures and in Vivo

Dermentzaki

Paschalidis

Politis

et al. 2016

Journal of Biological Chemistry

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␣-Synuclein, a presynaptic neuronal protein encoded by the SNCA gene, is strongly implicated in Parkinson disease (PD). PD pathogenesis is linked to increased SNCA levels; however, the transcriptional elements that control SNCA expression are still elusive. Previous experiments in PC12 cells demonstrated that the transcription factor zinc finger and SCAN domain containing 21 (ZSCAN21) plays an important regulatory role in SNCA transcription. Currently, we characterized the role of ZSCAN21 in SNCA transcription in primary neuronal cultures and in vivo. We found that ZSCAN21 is developmentally expressed in neurons in different rat brain regions. We confirmed its binding in the intron 1 region of SNCA in rat cortical cultures. Lentivirusmediated silencing of ZSCAN21 increased significantly SNCA promoter activity, mRNA, and protein levels in such cultures. In contrast, ZSCAN21 silencing reduced SNCA in neurosphere cultures. Interestingly, ZSCAN21 overexpression in cortical neurons led to robust mRNA but negligible protein expression, suggesting that ZSCAN21 protein levels are tightly regulated post-transcriptionally and/or post-translationally in primary neurons. Efficient adeno-associated virus-mediated knockdown of ZSCAN21 in the postnatal and adult hippocampus, an area linked with non-motor PD symptoms, revealed no significant alterations in SNCA levels. Overall, our study demonstrates that ZSCAN21 is involved in the transcriptional regulation of SNCA in primary neuronal cultures, but the direction of the effect is variable, likely depending on neuronal maturation. However, the unaltered SNCA levels observed following ZSCAN21 downregulation in the rat brain, possibly due to compensatory mechanisms, imply that ZSCAN21 is not a master regulator of SNCA in vivo.Genetic alterations in SNCA are closely linked to familial and sporadic PD.2 Several lines of evidence have directly linked increased levels of wild type SNCA with dysfunctional and abnormal SNCA deposition and neurodegeneration in animal models and in humans, whereas polymorphisms within and around the SNCA gene locus are correlated to increased risk of PD (1). Importantly, large unbiased genome-wide association studies established single nucleotide polymorphisms in the SNCA region as one of the most common risk factors for sporadic PD (2-6). Collectively, these studies support the overarching idea that dysregulation of SNCA levels, leading to its excess accumulation and aggregation, is a major factor in PD pathogenesis. Nonetheless, to date not much is known about the regulation of SNCA levels in general, let alone its transcriptional regulation. From previous studies it is well established that under physiological conditions SNCA mRNA levels are developmentally induced in the rat brain (7). The mechanisms involved in the developmental transcriptional regulation of SNCA remain elusive. Conversely, under pathological conditions in PD there has been controversy regarding the expression levels of SNCA mRNA in the brains of sporadic PD patients, with studies re...

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confidence: 98%

Complex Effects of the ZSCAN21 Transcription Factor on Transcriptional Regulation of α-Synuclein in Primary Neuronal Cultures and in Vivo

Dermentzaki

Paschalidis

Politis

et al. 2016

Journal of Biological Chemistry

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“…They showed that ZSCAN21 binds to intron1 of SNCA as expected, but also that GATA-2 specifically binds to the intron2 region while C/EBPβ doesn’t demonstrate a significant binding at any of its four putative binding sites in the SNCA promoter in any different brain regions studied (Brenner et al , 2015). The expression of ZSCAN21 in different brain regions was found to be very low as compared to two other transcription factors.…”

Section: Regulation Of α-Synuclein Expression and Parkinson’s Diseasementioning

confidence: 65%

“…Recently, Brenner et al studied the three transcription factors C/EBPβ, GATA-2, and ZSCAN21 in PD patients and post-mortem brain samples (Brenner et al , 2015). They showed that ZSCAN21 binds to intron1 of SNCA as expected, but also that GATA-2 specifically binds to the intron2 region while C/EBPβ doesn’t demonstrate a significant binding at any of its four putative binding sites in the SNCA promoter in any different brain regions studied (Brenner et al , 2015).…”

Section: Regulation Of α-Synuclein Expression and Parkinson’s Diseasementioning

confidence: 99%

Deregulation of α-synuclein in Parkinson’s disease: Insight from epigenetic structure and transcriptional regulation of SNCA

Guhathakurta

Bok

Evangelista

et al. 2017

Progress in Neurobiology

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Understanding regulation of α-synuclein has long been a central focus for Parkinson’s disease (PD) researchers. Accumulation of this protein in the Lewy body or neurites, mutations in the coding region of the gene and strong association of α-synuclein encoding gene multiplication (duplication/triplication) with familial form of PD have indicated the importance of this molecule in pathogenesis of the disease. Several years of research identified many potential faulty pathways associated with accumulation of α-synuclein inside dopaminergic neurons and its transmission to neighboring ones. Concurrently, an appreciable body of research is growing to understand the epigenetic and genetic deregulation of α-synuclein that might contribute to the disease pathology. Completion of the ENCODE (Encyclopedia of DNA Elements) project and recent advancement made in the epigenetic and trans factor mediated regulation of each gene, has tremendously accelerated the need to carefully understand the epigenetic structure of the gene (SNCA) encoding α-synuclein protein in order to decipher the regulation and contribution of α-synuclein to the pathogenesis of PD. We have also analyzed the detailed epigenetic structure of this gene with knowledge from ENCODE database, which may open new avenues in α-synuclein research. Interestingly, we have found that the gene contains several transcriptionally activate histone modifications and associated potential transcription factor binding sites in the non-coding areas that strongly suggest alternative regulatory pathways. Altogether this review will provide interesting insight of α-synuclein gene regulation from epigenetic, genetic and post-transcriptional perspectives and their potential implication in the PD pathogenesis.

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“…Thus, as a representative of the GATA family, we selected GATA1 to investigate the effects of repeats on its DNA binding affinity. Interestingly, members of both GATA and ELK transcription factor families play important roles in brain development and function[30] and some have even been shown to regulate the expression of the SNCA gene[31, 32], albeit through regulatory regions distinct from the Rep1 region studied here. Thus, the proximity of ELK and GATA binding sites to the Rep1 region, together with the known effects of Rep1 alleles on SNCA gene expression, led us to hypothesize that the length of different repeat units that comprise the Rep1 region could have a direct influence on ELK and/or GATA binding at this genomic site.…”

Section: Resultsmentioning

confidence: 99%

“…Noteworthy, other groups have shown that GATA TFs bind to elements within intron 1 [31] and the promoter [32] of SNCA , where they have been proposed to play a role as inducers of transcription. Consistently with these previous reports, we showed that, among the GATA family members, GATA2 is highly abundant in human cortex, suggesting that GATA2 plays a role in the regulation of SNCA transcription.…”

Section: Discussionmentioning

confidence: 99%

Toward deciphering the mechanistic role of variations in the Rep1 repeat site in the transcription regulation of SNCA gene

et al. 2018

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Short structural variants – variants other than single nucleotide polymorphisms – are hypothesized to contribute to many complex diseases, possibly by modulating gene expression. However, the molecular mechanisms by which noncoding short structural variants exert their effects on gene regulation haven’t been discovered. Here, we study simple sequence repeats (SSR), a common class of short structural variants. Previously, we showed that repetitive sequences can directly influence the binding of transcription factors to their proximate recognition sites, a mechanism we termed non-consensus binding. In this study, we focus on the SSR termed Rep1, which was associated with Parkinson’s disease (PD) and has been implicated in the cis-regulation of the PD-risk SNCA gene. We show that Rep1 acts via the non-consensus binding mechanism to affect the binding of transcription factors from the GATA and ELK families to their specific sites located right next to the Rep1 repeat. Next, we performed an expression analysis to further our understanding regarding the GATA and ELK family members that are potentially relevant for SNCA transcriptional regulation in health and disease. Our analysis indicates a potential role for GATA2, consistent with previous reports. Our study proposes non-consensus transcription factor binding as a potential mechanism through which noncoding repeat variants could exert their pathogenic effects by regulating gene expression.

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Transcriptional regulation of the α-synuclein gene in human brain tissue

Cited by 21 publications

References 23 publications

Complex Effects of the ZSCAN21 Transcription Factor on Transcriptional Regulation of α-Synuclein in Primary Neuronal Cultures and in Vivo

Complex Effects of the ZSCAN21 Transcription Factor on Transcriptional Regulation of α-Synuclein in Primary Neuronal Cultures and in Vivo

Deregulation of α-synuclein in Parkinson’s disease: Insight from epigenetic structure and transcriptional regulation of SNCA

Toward deciphering the mechanistic role of variations in the Rep1 repeat site in the transcription regulation of SNCA gene

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