Genetic variability in the
            <i>SNCA</i>
            gene influences α‐synuclein levels in the blood and brain

Fuchs, Julia; Tichopád, Aleš; Golub, Yulia; Munz, Marita; Schweitzer, Katherine J.; Wolf, Björn; Berg, Daniela; Mueller, Jakob C.; Gasser, Thomas

doi:10.1096/fj.07-9348com

Cited by 242 publications

(212 citation statements)

References 34 publications

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“…SNCA protein levels were measured from peripheral blood mononuclear cells using ELISA (Human Alpha-Synuclein Immunoassay Kit, Biosource Europe). The ratio of SNCA protein (ng/mL) and total protein (g/mL) was calculated to compare duplication carriers and noncarriers (19).…”

Section: Discussionmentioning

confidence: 99%

α-Synuclein gene duplication impairs reward learning

Kéri

Moustafa

Myers

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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α-Synuclein (SNCA) plays an important role in the regulation of dopaminergic neurotransmission and neurodegeneration in Parkinson disease. We investigated reward and punishment learning in asymptomatic carriers of a rare SNCA gene duplication who were healthy siblings of patients with Parkinson disease. Results revealed that healthy SNCA duplication carriers displayed impaired reward and intact punishment learning compared with noncarriers. These results demonstrate that a copy number variation of the SNCA gene is associated with selective impairments on reinforcement learning in asymptomatic carriers without the motor symptoms of Parkinson disease.Parkinson disease | reinforcement learning | dopamine | basal ganglia I t has been demonstrated that the copy number variation of the α-synuclein gene (SNCA), which encodes a protein regulating dopamine turnover in the presynaptic terminal, causes Parkinson disease (1). The multiplication of the SNCA locus is very rare; beyond the few families reported in the literature (2), Ahn et al. (3) identified three patients with duplication from 1,106 screened individuals with parkinsonism. Each patient had biological relatives who were asymptomatic carriers. However, the penetrance of SNCA duplication is not exactly defined, and its behavioral consequences in asymptomatic carriers are unknown (4).The protein encoded by the SNCA gene may serve as a regulator of the mesolimbic dopaminergic system and hence might play an important role in reward learning. Oksman et al. (5) showed that the absence of SNCA resulting from a spontaneous mutation in C57BL/6J mice enhanced operant behavior during intracranial self-stimulation, suggesting that the lack of SNCA sensitized the reward system of the brain. Transgenic mice overexpressing A30P-mutated SNCA exhibit reduced locomotor activity and smaller evoked dopamine release in the striatum (6). Evidence from a positron emission tomography study in humans suggests that high dopamine synthesis in the striatum results in better reversal learning from reward than from punishment, whereas low baseline dopamine synthesis is associated with the opposite pattern of performance (7).In this study, we aimed to investigate the possible reinforcement learning phenotype of SNCA multiplication and overexpression in humans. We assessed seven asymptomatic healthy carriers of SNCA duplication who later developed Parkinson disease and 10 noncarrier comparison participants on a reward-and punishmentguided A/B probabilistic classification learning task. Participants could win or lose imaginary quarter dollars by deciding whether abstract images belong to category A or B (Fig. 1A). On reward trials, correct responses were followed by a 25-point gain. On punishment trials, incorrect responses were followed by a 25-point loss. Some images belonged to category A with 80% probability and to category B with 20% probability, whereas others had the opposite category probability. On some trials, feedback was not provided. Reward learning was also assessed with an ind...

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Section: Discussionmentioning

confidence: 99%

α-Synuclein gene duplication impairs reward learning

Kéri

Moustafa

Myers

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…NCSCs from controls, heterozygous GBA mutation positive carriers and PD subjects were differentiated for 40 days to DA neurons, and SNCA levels were measured by western blot. It is known that differences in expression levels of SNCA are influenced by individual genetic background, which could explain the high variability of SNCA expression in the general population (Fuchs et al, 2008). I measured SNCA levels in neuronal cultures from GBA mutation positive NCSC-derived neurons and corresponding GBA negative controls.…”

Section: Increased α-Synuclein Levels In Gba Mutant Neuronsmentioning

confidence: 99%

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Beavan

Schapira

2013

Annals of Medicine

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“…4 Recent genome-wide association studies in PD pointed to the 3 0 end of SNCA, which had already been implicated in the regulation of SNCA expression. [5][6][7] The 3 0 untranslated region (UTR) of SNCA carries various putative microRNA (miRNA) -binding sites that could have a role in SNCA expression and thus contribute to the susceptibility to develop PD. 8,9 We hypothesized that variants located within the 3 0 UTR might influence the expression of SNCA by modulating translation or mRNA stability.…”

Section: Introductionmentioning

confidence: 99%

Variants in the 3′UTR of SNCA do not affect miRNA-433 binding and alpha-synuclein expression

et al. 2012

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Alpha-synuclein (SNCA) is a major risk gene for Parkinson's disease (PD) and increased SNCA gene dosage results in a parkinsonian syndrome in affected families. Regulatory regions relevant for SNCA expression include the 3 0 untranslated region (UTR), which among other regulatory elements contains several micro-RNA-binding sites. Interestingly, variants located in the 3 0 region of SNCA have been associated with PD in two genome-wide association studies. To test whether private mutations in this region contribute to PD, we sequenced the 3 0 UTR of SNCA in 1285 PD patients and 1120 age/sex-matched healthy controls. We found two rare variants, the one corresponding to the single nucleotide polymorphism rs145304567 and the novel variant c.*1004_1008delTTTTT. Although rs145304567 affects the putative-binding site of microRNA (miRNA) -433, the allele distribution was similar in PD patients and controls, and the expression of SNCA mRNA was not related to the genotype. Furthermore, a regulatory effect of miRNA-433 on SNCA expression levels was not detected.

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Genetic variability in the SNCA gene influences α‐synuclein levels in the blood and brain

Cited by 242 publications

References 34 publications

α-Synuclein gene duplication impairs reward learning

α-Synuclein gene duplication impairs reward learning

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Variants in the 3′UTR of SNCA do not affect miRNA-433 binding and alpha-synuclein expression

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