We analyzed whether genetic variation of alpha-synuclein modulates the extent of neuropathological changes in a population-based autopsied sample of 272 elderly Finns. None of the 11 markers was associated with the extent of neocortical beta-amyloid pathology. The intron 4 marker rs2572324 was associated with the extent of neurofibrillary pathology (p = 0.0006, permuted p = 0.004; Braak stages IV-VI vs 0-II). The same variant also showed a trend for association with neocortical Lewy-related pathology. These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration.
"Neurofibrillary tau pathology is modulated by genetic variations of αSyn . Tau phosphorylation is found in synapse-enriched fractions of frontal cortex in PD and AD  and in brainstems of αSyn mice . "
[Show abstract][Hide abstract] ABSTRACT: Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.
The Scientific World Journal 10/2011; 11(2, article 5):1893-907. DOI:10.1100/2011/371893 · 1.73 Impact Factor
"We used (Supplementary Fig. 1): (i) 288 controls from Finland and 285 controls from Switzerland without neurological conditions, recruited and genotyped for this study; (ii) 1165 USA controls from the Duke Memory study (Need et al., 2009; Cirulli et al., 2010), who consented to participate in epilepsy genetics research; 84% of participants filled in a questionnaire about their history of neurological conditions and the subjects who reported a history of seizures were excluded from the study; (iii) 5667 population controls from the Wellcome Trust Case Control Consortium (2007) Phase 2, September 2009 data release; (iv) 469 population controls from Finland, all 85-years-old or over at the time of recruitment (Vantaa85+) (Myllykangas et al., 2005; Peuralinna et al., 2008); and (v) 211 Irish neurologically-normal controls from the Study of Irish Amyotrophic Lateral Sclerosis (Cronin et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.
"We combined results of the population-based Vantaa 85þ study cohort with the hospital-based Helsinki cohort because this large Finnish study only included patients with delirium (cases) without controls. The Vantaa 85þ study [Rahkonen et al., 2001; Peuralinna et al., 2008] is a population based health survey focused on the clinical epidemiology and pathology of dementia and related cognitive disorders. The basic population consisted of all people (n ¼ 601) born before April 1906 living in the city of Vantaa, Southern Finland on April 1991. "
[Show abstract][Hide abstract] ABSTRACT: Delirium is the most common neuropsychiatric syndrome in elderly ill patients. Previously, associations between delirium and the dopamine transporter gene (solute carrier family 6, member 3 (SLC6A3)) and dopamine receptor 2 gene (DRD2) were found. The aim of this study was to validate whether markers of the SLC6A3 and DRD2 genes are were associated with delirium in independent populations. Six European populations collected DNA of older delirious patients. Associations were determined per population and results were combined in a meta-analysis. In total 820 medical inpatients, 185 cardiac surgery patients, 134 non-cardiac surgery patients and 502 population-based elderly subjects were included. Mean age was 82 years (SD 7.5 years), 598 (36%) were male, 665 (41%) had pre-existing cognitive impairment, and 558 (34%) experienced delirium. The SLC6A3 rs393795 homozygous AA genotype was more frequent in patients without delirium in all populations. The meta-analysis showed an Odds Ratio (OR) for delirium of 0.4 (95% confidence interval (C.I.) 0.2-0.6, P = 0.0003) for subjects with AA genotype compared to the AG and GG genotypes. SLC6A3 marker rs1042098 showed no association with delirium. In meta-analysis the DRD2 rs6276 homozygous GG genotype showed an OR of 0.8 for delirium (95% C.I. 0.6-1.1, P = 0.24). When subjects were stratified for cognitive status the rs6276 GG genotype showed ORs of 0.6 (95% C.I. 0.4-1.0, P = 0.06) and 0.8 (95% C.I. 0.5-1.5, P = 0.51) for delirium in patients with and without cognitive impairment, respectively. In independent cohorts, a variation in the SLC6A3 gene and possibly the DRD2 gene were found to protect for delirium.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2009; 153B(2):648-55. DOI:10.1002/ajmg.b.31034 · 3.42 Impact Factor
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