[Show abstract][Hide abstract] ABSTRACT: Aims:
Protein aggregation and oxidative stress are both key pathogenic processes in Parkinson's disease, although the mechanism by which misfolded proteins induce oxidative stress and neuronal death remains unknown. In this study we describe how aggregation of alpha-synuclein from its monomeric form to its soluble oligomeric state results in aberrant free radical production and neuronal toxicity.
We first demonstrate excessive free radical production in a human iPS derived alpha-synuclein triplication model at basal levels and on application of picomolar doses of -sheet-rich alpha-synuclein oligomers. We probed the effects of different structural species of alpha-synuclein in wildtype rat neuronal cultures, and show that both oligomeric and fibrillar forms of alpha-synuclein are capable of generating free radical production, but that only the oligomeric form results in reduction of endogenous glutathione and subsequent neuronal toxicity. We dissected the mechanism of oligomer induced free radical production and found that it was interestingly independent of all known cellular enzymatic sources.
the oligomer induced ROS production was entirely dependent on the presence of free metal ions, as addition of metal chelators was able to block oligomer-induced ROS production and prevent oligomer-induced neuronal death.
Our findings further support the causative role of soluble amyloid oligomers in triggering neurodegeneration and shed light into the mechanisms by which these species cause neuronal damage, which, we show here, can be amenable to modulation through the use of metal chelation.
Antioxidants and Redox Signaling 11/2015; DOI:10.1089/ars.2015.6343 · 7.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe the isolation and detailed structural characterization of stable toxic oligomers of α-synuclein that have accumulated during the process of amyloid formation. Our approach has allowed us to identify distinct subgroups of oligomers and to probe their molecular architectures by using cryo-electron microscopy (cryoEM) image reconstruction techniques. Although the oligomers exist in a range of sizes, with different extents and nature of β-sheet content and exposed hydrophobicity, they all possess a hollow cylindrical architecture with similarities to certain types of amyloid fibril, suggesting that the accumulation of at least some forms of amyloid oligomers is likely to be a consequence of very slow rates of rearrangement of their β-sheet structures. Our findings reveal the inherent multiplicity of the process of protein misfolding and the key role the β-sheet geometry acquired in the early stages of the self-assembly process plays in dictating the kinetic stability and the pathological nature of individual oligomeric species.
Proceedings of the National Academy of Sciences 04/2015; 112(16):E1994-E2003. DOI:10.1073/pnas.1421204112 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
We have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset.Methods
This study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta-analysis of PD genome-wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset.ResultsOur polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome-wide association cohorts (minimum p = 3.76 × 10−6). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p = 0.00014).InterpretationThis provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes. Ann Neurol 2015
Annals of Neurology 03/2015; 77(4). DOI:10.1002/ana.24335 · 9.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The catechol-O-methyltransferase (COMT) enzyme is a major determinant of prefrontal dopamine levels. The Val158Met polymorphism affects COMT enzymatic activity and has been associated with variation in executive function and affective
processing. This study investigated the effect of COMT genotype on the flexible modulation of the balance between processing self-generated and processing stimulus-oriented information,
in the presence or absence of affective distractors. Analyses included 124 healthy adult participants, who were also assessed
on standard working memory (WM) tasks. Relative to Val carriers, Met homozygotes made fewer errors when selecting and manipulating
self-generated thoughts. This effect was partly accounted for by an association between COMT genotype and visuospatial WM performance. We also observed a complex interaction between the influence of affective distractors,
COMT genotype and sex on task accuracy: male, but not female, participants showed a sensitivity to the affective distractors that
was dependent on COMT genotype. This was not accounted for by WM performance. This study provides novel evidence of the role of dopaminergic genetic
variation on the ability to select and manipulate self-generated thoughts. The results also suggest sexually dimorphic effects
of COMT genotype on the influence of affective distractors on executive function.
Social Cognitive and Affective Neuroscience 09/2014; 10(6). DOI:10.1093/scan/nsu118 · 7.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
[Show abstract][Hide abstract] ABSTRACT: We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.
[Show abstract][Hide abstract] ABSTRACT: Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children's ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child's cognitive abilities at age twelve.
[Show abstract][Hide abstract] ABSTRACT: Working memory (WM) refers to mental processes that enable temporary retention and manipulation of information, including information about other people ("social working memory"). Previous studies have demonstrated that nonsocial WM is supported by dopamine neurotransmission. Here, we investigated in 131 healthy adults whether dopamine is similarly involved in social WM by testing whether social and nonsocial WM are influenced by genetic variants in three genes coding for molecules regulating the availability of dopamine in the brain: catechol-O-methyltransferase (COMT), dopamine active transporter (DAT), and monoamine-oxidase A (MAOA). An advantage for the Met allele of COMT was observed in the two standard WM tasks and in the social WM task. However, the influence of COMT on social WM performance was not accounted for by its influence on either standard WM paradigms. There was no main effect of DAT1 or MAOA, but a significant COMT x DAT1 interaction on social WM performance. This study provides novel preliminary evidence of effects of genetic variants of the dopamine neurotransmitter system on social cognition. The results further suggest that the effects observed on standard WM do not explain the genetic effects on effortful social cognition.
Social Neuroscience 06/2014; 9(5):1-15. DOI:10.1080/17470919.2014.925503 · 2.66 Impact Factor