Mini review: linkage between α-Synuclein protein and cognition

Saleh, Huda; Saleh, Ayeh; Yao, Hailan; Cui, Jie; Shen, Yong; Li, Rena

doi:10.1186/s40035-015-0026-0

Cited by 12 publications

(9 citation statements)

References 42 publications

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“…First, ZSCAN21 is adequately expressed in this area. Second, hippocampus is an area mainly linked with the non-motor symptoms of PD, including primarily cognitive impairment and dementia that affect a high percentage of PD patients (56,57). Additionally, hippocampal accumulation of SNCA has been reported to be involved in the pathogenesis of PD and other synucleinopathies (57), suggesting that the regulation of SNCA expression in this region may be of critical importance.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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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“…Our primary hypothesis was that cognitive decline is associated with an abrogation of normal epoxy fatty acid status based on findings that inhibition of soluble epoxide hydrolase, an enzyme previously implicated in the regulation of microvascular tone and inflammation, protects hippocampal neuronal death and reduces cognitive decline in mice 7 , and that genetic deletion of this enzyme slows amyloid beta associated Alzheimer’s disease onset in mice 8 . Further studies have shown that sEH inhibition reduces neuroinflammation 9 and alpha-synuclein aggregation 10 , 11 , pathological feature of multiple neurocognitive disorders 12 .…”

Section: Introductionmentioning

confidence: 99%

Serum metabolomic biomarkers of perceptual speed in cognitively normal and mildly impaired subjects with fasting state stratification

Borkowski

Taha

Pedersen

et al. 2021

Sci Rep

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Cognitive decline is associated with both normal aging and early pathologies leading to dementia. Here we used quantitative profiling of metabolites involved in the regulation of inflammation, vascular function, neuronal function and energy metabolism, including oxylipins, endocannabinoids, bile acids, and steroid hormones to identify metabolic biomarkers of mild cognitive impairment (MCI). Serum samples (n = 212) were obtained from subjects with or without MCI opportunistically collected with incomplete fasting state information. To maximize power and stratify the analysis of metabolite associations with MCI by the fasting state, we developed an algorithm to predict subject fasting state when unknown (n = 73). In non-fasted subjects, linoleic acid and palmitoleoyl ethanolamide levels were positively associated with perceptual speed. In fasted subjects, soluble epoxide hydrolase activity and tauro-alpha-muricholic acid levels were negatively associated with perceptual speed. Other cognitive domains showed associations with bile acid metabolism, but only in the non-fasted state. Importantly, this study shows unique associations between serum metabolites and cognitive function in the fasted and non-fasted states and provides a fasting state prediction algorithm based on measurable metabolites.

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“…SNCA ( PARK1 ) that encodes α-syn was the first gene identified to be associated with familial PD [ 34 , 35 ]. α-syn is a major component of cytoplasmic inclusions (LBs) in survived DA neurons in PD brain [ 36 , 37 ]. α-syn is highly enriched in presynaptic terminals [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction in Parkinson’s disease

Wang

2016

Transl Neurodegener

138

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Parkinson’s disease (PD) is the second most common neurodegenerative disease, which is characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites in surviving DA neurons in most cases. Although the cause of PD is still unclear, the remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis. Numerous studies showed that dysfunction of mitochondria may play key roles in DA neuronal loss. Both genetic and environmental factors that are associated with PD contribute to mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provides direct evidence linking mitochondrial dysfunction to PD. Decrease of mitochondrial complex I activity is present in PD brain and in neurotoxin- or genetic factor-induced PD cellular and animal models. Moreover, PINK1 and parkin, two autosomal recessive PD gene products, have important roles in mitophagy, a cellular process to clear damaged mitochondria. PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy. In this review, we summarize the factors associated with PD and recent advances in understanding mitochondrial dysfunction in PD.

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Mini review: linkage between α-Synuclein protein and cognition

Cited by 12 publications

References 42 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

Serum metabolomic biomarkers of perceptual speed in cognitively normal and mildly impaired subjects with fasting state stratification

Mitochondrial dysfunction in Parkinson’s disease

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