Synucleins and Gene Expression: Ramblers in a Crowd or Cops Regulating Traffic?

Surguchev, Alexei; Surguchov, Andrei

doi:10.3389/fnmol.2017.00224

Cited by 54 publications

(53 citation statements)

References 92 publications

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“…Although the ORs associated with SNCA SNPs were relatively low, previous research has suggested that functional SNCA SNPs can affect SNCA expression through epigenetic modification (Soldner et al, 2016 ), which may allow them to be used as potential therapeutic targets and to contribute to precise treatment strategy design (Carlson, 1990 ). These polymorphisms in SNCA may also possibly affect the risk of PD by damaging the normal function of α-synuclein by affecting synaptic activity through modulating the release of synaptic vesicle (Surguchev and Surguchov, 2017 ). Substitution of amino acids ofα-synuclein changed the gene expression levels including genes functioning in apoptosis, transcription process, membrane proteins, etc.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Analysis of the Association Between SNCA Polymorphisms and the Risk of Parkinson's Disease

Zhang

Sun

et al. 2018

Front. Mol. Neurosci.

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Background: Various studies have reported associations between synuclein alpha (SNCA) polymorphisms and Parkinson's disease (PD) risk. However, the results are inconsistent. We conducted a comprehensive meta-analysis of the associations between SNCA single-nucleotide polymorphisms (SNPs) and PD risk in overall populations and subpopulations by ethnicity.Methods: Standard meta-analysis was conducted according to our protocol with a cutoff point of p < 0.05. To find the most relevant SNCA SNPs, we used a cutoff point of p < 1 × 10−5 in an analysis based on the allele model. In the subgroup analysis by ethnicity, we divided the overall populations into five ethnic groups. We conducted further analysis on the most relevant SNPs using dominant and recessive models to identify the contributions of heterozygotes and homozygotes regarding each SNP.Results: In our comprehensive meta-analysis, 24,075 cases and 22,877 controls from 36 articles were included. We included 16 variants in the meta-analysis and found 12 statistically significant variants with p < 0.05. After narrowing down the variants using the p < 1 × 10−5 cutoff, in overall populations, seven SNPs increased the risk of PD (rs2736990, rs356220, rs356165, rs181489, rs356219, rs11931074, and rs2737029, with odds ratios [ORs] of 1.22–1.38) and one SNP decreased the risk (rs356186, with an OR of 0.77). In the East Asian group, rs2736990 and rs11931074 increased the risk (with ORs of 1.22–1.34). In the European group, five SNPs increased the risk (rs356219, rs181489, rs2737029, rs356165, and rs11931074, with ORs of 1.26–1.37) while one SNP decreased the risk (rs356186, with an OR of 0.77). The heterozygotes and homozygotes contributed differently depending on the variant.Conclusions: In summary, we found eight SNCA SNPs associated with PD risk, which had obvious differences between ethnicities. Seven SNPs increased the risk of PD and one SNP decreased the risk in the overall populations. In the East Asian group, rs2736990 and rs11931074 increased the risk. In the European group, rs356219, rs181489, rs2737029, rs356165, and rs11931074 increased the risk while rs356186 decreased the risk. Variants with the highest ORs and allele frequencies in our analysis should be given priority when carrying out genetic screening.

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Section: Discussionmentioning

confidence: 99%

A Comprehensive Analysis of the Association Between SNCA Polymorphisms and the Risk of Parkinson's Disease

Zhang

Sun

et al. 2018

Front. Mol. Neurosci.

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“…These groups have shown that reducing α-synuclein expression leads to reductions in dopaminergic neuron loss alongside fewer motor deficits. Thought, it is crucial to consider that blocking the expression of α-synuclein may interfere with the normal function of this protein (Surguchev and Surguchov, 2017;Burré et al, 2018;Sorrentino et al, 2019;Taguchi et al, 2019).…”

Section: Neurotrophic Factorsmentioning

confidence: 99%

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Iarkov

Barreto

Grizzell

et al. 2020

Front. Aging Neurosci.

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Parkinson's disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.

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“…α‐Synuclein is localized to neuronal presynaptic terminals and is made up of 140 amino acids and is encoded by the SNCA gene on the long arm of chromosome 4q21.3–q22, which spans 111 kb in length . Whilst still a subject of intense research, α‐synuclein is believed to regulate vesicle trafficking and refilling, endocytosis and neurotransmitter release via interactions with the soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) complex (both t‐SNARE and v‐SNARE) [, reviewed in ]. Aberrant α‐synuclein expression/conformation/localization may therefore impair neurotransmission in MPS IIIA brain .…”

Section: Introductionmentioning

confidence: 99%

“…Aberrant α‐synuclein expression/conformation/localization may therefore impair neurotransmission in MPS IIIA brain . Nuclear localization indicates an additional role in the modulation of protein expression .…”

Section: Introductionmentioning

confidence: 99%

Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking α‐synuclein

Soe

Beard

Neumann

et al. 2019

Neuropathology Appl Neurobio

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2019)Neuropathology and Applied Neurobiology 45, 715-731 Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking a-synuclein Background: Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is an inherited paediatric-onset neurodegenerative disorder caused by the lysosomal deficiency of sulphamidase with subsequent accumulation of heparan sulphate. The pathological mechanisms responsible for clinical disease are unknown; however, intraneuronal accumulation of aggregation-prone proteins such as a-synuclein, phosphorylated tau and amyloid precursor protein suggests inefficient intracellular trafficking and lysosomal degradation. Aim: To investigate the contribution the accumulating a-synuclein plays in early symptom emergence that is, impaired cognition, reduced anxiety and motor deficits, first detectable between 3-5 months of age. Methods: We have crossed congenic MPS IIIA mice with a-synuclein-deficient (Snca tm1Rosl /J) mice and evaluated phenotype and brain disease lesions. Results: In a battery of behavioural tests performed on mice aged 12-22 weeks, we were unable to differentiate a-synuclein-deficient MPS IIIA mice from those with one or both copies of the a-synuclein gene; all three affected genotypes were significantly impaired in test performance when compared to wildtype littermates. Histological studies revealed that the rate, location and nature of deposition of other proteinaceous lesions, the disruption to endolysosomal protein expression and the inflammatory response seen in the brain of a-synuclein-deficient MPS IIIA mice reflected that seen in MPS IIIA mice homo-or heterozygous for a-synuclein. Conclusion: Deletion and/or deficiency of a-synuclein does not influence clinical and neuropathological disease progression in murine MPS IIIA, demonstrating that in and of itself, this protein does not initiate the cognitive and motor symptoms that occur in the first 5 months of life in MPS IIIA mice.

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Synucleins and Gene Expression: Ramblers in a Crowd or Cops Regulating Traffic?

Cited by 54 publications

References 92 publications

A Comprehensive Analysis of the Association Between SNCA Polymorphisms and the Risk of Parkinson's Disease

A Comprehensive Analysis of the Association Between SNCA Polymorphisms and the Risk of Parkinson's Disease

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking α‐synuclein

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