α-Synuclein gene duplication is present in sporadic Parkinson disease

Ahn, Tae-Beom; Kim, S. Y.; Kim, J. Y.; Park, Sung Sup; Lee, D. S.; Min, Hosung; Kim, Y. K.; Kim, S. E.; Kim, J. M.; Kim, H. J.; Cho, J.; Jeon, Beom S.

doi:10.1212/01.wnl.0000271080.53272.c7

Cited by 222 publications

(159 citation statements)

References 24 publications

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“…reported with negative phenotypes for motor symptoms, olfaction, and rapid eye movement sleep behavior (3,4). Here, we show, in this rare nonelderly sample, that carriers display reward learning deficits that may precede the development of clinical motor symptoms, providing a unique opportunity to further explore the nature of the premotor stage of Parkinson disease and to develop early biomarkers.…”

Section: Discussionmentioning

confidence: 70%

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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: 70%

“…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.…”

mentioning

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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“…In addition, we identified a subject (III4) at a paucisymptomatic stage of the disease; the subject carried the SNCA locus duplication and displayed an asymmetric dopaminergic defect in DaTSCAN SPECT images. Hypo-uptake has not been observed in the other asymptomatic SNCA duplication carriers (Ahn et al, 2008). The disease being age-dependant, this difference might be explained by their younger age (from 44 to 51).…”

Section: Discussionmentioning

confidence: 78%

SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes

et al. 2011

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Genomic multiplication of the alpha-synuclein gene (SNCA) locus is one cause of familial Parkinson disease (PD). We performed detailed genomic, SNCA expression level, clinical, neuropsychological and functional imaging analyses of a parkinsonian kindred with a known duplication of the SNCA locus. We demonstrated that the duplication spanned 4.928 Mb (encompassing 31 known and putative genes) and was the largest to have been described at this locus. The presence of several repetitive long interspersed nuclear elements (LINEs) flanking the potential break area suggested that the duplication resulted from a genomic recombination between LINEs. We sequenced the break junction and confirmed the involvement of L1PA2 and L1PA4 in a non-allelic, homologous recombination. An analysis of mRNA levels in immortalized lymphoblastoid cells and peripheral blood mononuclear cells showed SNCA overexpression in subjects with the duplication, as well as overexpression of 13 other genes highlighting the usefulness of such cell models to study this duplication. Interestingly, abnormal tracer uptake in DaTSCAN ® imaging correlated with the severity of the clinical symptoms. Our detailed genomic analysis and clinical exploration enabled us to specify the genotype-phenotype relationship, identify a case of presymptomatic PD and gain insight into the role of LINEs in SNCA locus duplication.

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“…At present there are three known mutants of aS associated with Parkinsonism, A53T, 7 A30P, 8 and E46K. 9 Furthermore, duplication 10,11 or triplication 12 of the aS gene leading to overexpression of the protein can also cause PD.…”

Section: Introductionmentioning

confidence: 99%

Charge neutralization and collapse of the C‐terminal tail of alpha‐synuclein at low pH

2009

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Alpha-synuclein (aS) is the primary component of Lewy bodies, the pathological hallmark of Parkinson's Disease. Aggregation of aS is thought to proceed from a primarily disordered state with nascent secondary structure through intermediate conformations to oligomeric forms and finally to mature amyloid fibrils. Low pH conditions lead to conformational changes associated with increased aS fibril formation. Here we characterize these structural and dynamic changes using solution state NMR measurements of secondary chemical shifts, relaxation parameters, residual dipolar couplings, and paramagnetic relaxation enhancement. We find that the neutralization of negatively charged side-chains eliminates electrostatic repulsion in the C-terminal tail of aS and leads to a collapse of this region at low pH. Hydrophobic contacts between the compact C-terminal tail and the NAC (non-amyloid-b component) region are maintained and may lead to the formation of a globular domain. Transient long-range contacts between the C-terminus of the protein and regions N-terminal to the NAC region are also preserved. Thus, the release of long-range contacts does not play a role in the increased aggregation of aS at low pH, which we instead attribute to the increased hydrophobicity of the protein.

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α-Synuclein gene duplication is present in sporadic Parkinson disease

Cited by 222 publications

References 24 publications

α-Synuclein gene duplication impairs reward learning

α-Synuclein gene duplication impairs reward learning

SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes

Charge neutralization and collapse of the C‐terminal tail of alpha‐synuclein at low pH

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