Dataset Information

The Length of SNCA Rep1 Microsatellite May Influence Cognitive Evolution in Parkinson's Disease.

ABSTRACT: Background:Alpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson's disease (PD). A previous study showed that a variant of the alpha-synuclein gene (SNCA), namely the 263?bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients. Methods:We recruited and genotyped for SNCA Rep1 426 PD patients with age at onset ?40?years and disease duration ?4?years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox's proportional hazards regression model. Results:SNCA Rep1 263 carriers showed significantly increased risk of both dementia (HR?=?3.03) and visual hallucinations (HR?=?2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups. Conclusion:SNCA Rep1 263 allele is associated with a worse cognitive outcome in PD.

SUBMITTER: Corrado L

PROVIDER: S-EPMC5890103 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Length of <i>SNCA</i> Rep1 Microsatellite May Influence Cognitive Evolution in Parkinson's Disease.

Corrado Lucia L De Marchi Fabiola F Tunesi Sara S Oggioni Gaia Donata GD Carecchio Miryam M Magistrelli Luca L Tesei Silvana S Riboldazzi Giulio G Di Fonzo Alessio A Locci Clarissa C Trezzi Ilaria I Zangaglia Roberta R Cereda Cristina C D'Alfonso Sandra S Magnani Corrado C Comi Giacomo P GP Bono Giorgio G Pacchetti Claudio C Cantello Roberto R Goldwurm Stefano S Comi Cristoforo C

Frontiers in neurology 20180329

<h4>Background</h4>Alpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson's disease (PD). A previous study showed that a variant of the alpha-synuclein gene (<i>SNCA</i>), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on ...[more]

PMID: 29662465

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Project description:Individual differences in dopaminergic tone underlie tendencies to learn from reward versus punishment. These effects are well documented in Parkinson's patients, who vacillate between low and high tonic dopaminergic states as a function of medication. Yet very few studies have investigated the influence of higher-level cognitive states known to affect downstream dopaminergic learning in Parkinson's patients. A dopamine-dependent cognitive influence over learning would provide a candidate mechanism for declining cognitive integrity and motivation in Parkinson's patients. In this report we tested the influence of two high-level cognitive states (cost of conflict and value of volition) that have recently been shown to cause predictable learning biases in healthy young adults as a function of dopamine receptor subtype and dopaminergic challenge. It was hypothesized that Parkinson's patients OFF medication would have an enhanced cost of conflict and a decreased value of volition, and that these effects would be remediated or reversed ON medication. Participants included N = 28 Parkinson's disease patients who were each tested ON and OFF dopaminergic medication and 28 age- and sex-matched controls. The expected cost of conflict effect was observed in Parkinson's patients OFF versus ON medication, but only in those that were more recently diagnosed (<5 years). We found an unexpected effect in the value of volition task: medication compromised the ability to learn from difficult a-volitional (instructed) choices. This novel finding was also enhanced in recently diagnosed patients. The difference in learning biases ON versus OFF medication between these two tasks was strongly correlated, bolstering the idea that they tapped into a common underlying imbalance in dopaminergic tone that is particularly variable in earlier stage Parkinsonism. The finding that these decision biases are specific to earlier but not later stage disease may offer a chance for future studies to quantify phenotypic expressions of idiosyncratic disease progression.

Project description:Intraneuronal inclusions of alpha-synuclein (α-synuclein, α-syn) are commonly found in the brain of patients with Parkinson's disease (PD). The pathogenesis of the abundant α-syn protein in the blood has been extensively studied to understand its properties better. In recent years, peptidome analysis has received increasing attention. In this study, we identified and analyzed serum peptides from wild-type (WT) and the (Thy-1)-h[A30P] alpha-synuclein transgenic mice (SNCA-A30P mice) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). One thousand eight hundred fifty-six peptides from 771 proteins were analyzed. Among them, 151 peptides from 107 proteins were significantly differentially expressed. The glycoprotein VI platelet pathway (GP6) was the pathway's most significant differentially expressed signaling pathway. Cleavage sites of the differentially expressed peptides may reflect protease distribution and activity. We selected the most significantly differentially expressed peptide, VGGDPI, and found that it contained cathepsin K (Ctsk) and trypsin-1 cleavage sites, suggesting that Ctsk and trypsin-1 may be key peptidases in PD. α-syn is a protein associated with the pathogenesis of PD. mutations in several genes, including SNCA, which encodes α-syn, are associated with the development of PD. Bioinformatics analysis of the physiological pathways related to SNCA genes and apoptosis genes found the five most markedly up-regulated proteins: formin homology 2 domain-containing 1 (FHOD1), insulin receptor substrate 1(IRS1), TRPM8 channel-associated factor 1 (TCAF1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and interleukin-16 (IL-16). Therefore, the differentially expressed peptides in the five precursor protein domains may be potential bioactive peptides associated with α-syn and apoptosis. This study provides a validated peptidomics profile of SNCA-A30P mice and identifies potentially bioactive peptides linked to α-syn and apoptosis.

Dataset Information

The Length of SNCA Rep1 Microsatellite May Influence Cognitive Evolution in Parkinson's Disease.

Publications

The Length of <i>SNCA</i> Rep1 Microsatellite May Influence Cognitive Evolution in Parkinson's Disease.

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