Parkinson's Disease Research Today is a free monthly online journal that collates and summarizes the latest research about Parkinson's Disease, including details on symptoms, treatment, genetics, medication. | ||||||
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Genetic association study of synphilin-1 in idiopathic Parkinson's disease.Myhre R, Klungland H, Farrer MJ, Aasly JO Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway. ronny.myhre@ntnu.no BACKGROUND: Post-mortem Lewy body and Lewy neuritic inclusions are a defining feature of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). With the discovery of missense and multiplication mutations in the alpha-synuclein gene (SNCA) in familial parkinsonism, Lewy inclusions were found to stain intensely with antibodies raised against the protein. Yeast-two-hybrid studies identified synphilin-1 as an interacting partner of alpha-synuclein, and both proteins show co-immunolocalization in a subset of Lewy body inclusions. In the present study, we have investigated whether common variability in synphilin-1, including coding substitutions are genetically associated with disease pathogenesis. METHODS: We screened the synphilin-1 gene for 11 single nucleotide polymorphisms (SNPs) in 300 affected subjects with idiopathic Parkinson's disease and 412 healthy controls. Six of these were rare variants including five previously identified amino acid substitutions that were chosen in a direct approach for association of rare disease causing mutations. An additional five highly heterozygous SNPs were chosen for an indirect association approach including haplotype analysis, based on the assumption that any disease causing mutations might be in linkage disequilibrium with the SNPs selected. We also genotyped a microsatellite marker (D5S2950) within intron 6 of the gene and five additional microsatellites clustered downstream of the 5p23.1-23.3 synphilin-1 locus. Genome-wide linkage analysis, in a number of independent studies, has previously highlighted suggestive linkage to PD in this region of chromosome 5. RESULTS: Screening of previously known amino acid substitutions in the synphilin-1 gene, identified the C1861>T (R621C) substitution in four patients (chromosomes n = 600) and 10 control subjects (chromosomes n = 824), whereas the G2125>C (E706Q) substitution was detected in one patient and four control subject, suggesting both these substitutions are not associated with susceptibility to PD. Heterozygous non-synonymous T131>C (V44A) and synonymous C636>T (P212P) amino acid substitutions were each detected in only one patient with PD. Heterozygous C1134>T (L378L) synonymous substitutions were found in two patients with PD and one control subject. D5S2010 the most distal telomeric microsatellite marker genotyped,15.3 Mb from synphilin-1, was genetically associated with PD (p = 0.006, 27df) independently adjusted for multiple testing according to its high amount of alleles but not the total number of other markers investigated. Other flanking and intronic SNP and microsatellite markers showed no evidence for genetic association with disease. CONCLUSION: In this study rare synphilin-1 SNPs were assessed in a direct association approach to identify amino acid substitutions that might confer risk of PD in a homozygous or compound heterozygous state. We found none of these rare variations were associated with disease. In contrast to prior studies the frequency of the R621C substitution was not significantly different between PD and control subjects, neither were the V44A or E706Q substitutions. Similarly, our indirect study of more heterozygous SNPs, including both single marker and haplotype analyses, showed no significant association to PD. However, marginal association of microsatellite alleles with idiopathic PD, within the chromosome 5q21 region, indicates further studies are warranted. Published 23 April 2008 in BMC Med Genet, 9: 19. Articles on Parkinson's Disease published 11 April 2008: Genetic variability of histamine receptors in patients with Parkinson's disease. BMC Med Genet, 9: 15. BACKGROUND: Changes in the density and expression of histamine receptors (HRH) have been detected in Parkinson's disease (PD) patients, and HRH antagonists bring about improvements in motor and other symptoms, thus suggesting that HRH play a role in the clinical response of PD patients. This study is aimed to analyse polymorphic variations of HRH in patients with PD. METHODS: Leukocytary DNA from 195 PD patients and a control group of 231 unrelated healthy individuals was studied for the ... [Abstract] [Full-text] Articles on Parkinson's Disease published 25 March 2008: Patterns and stages of alpha-synucleinopathy: Relevance in a population-based cohort. Neurology, 70(13): 1042-8. BACKGROUND: It is proposed that alpha-synucleinopathy (AS) initially affects the medulla oblongata and progresses to more rostral brain areas in a hierarchical sequence ("Braak hypothesis"). Predominant involvement of the amygdala is also described. This study examines the applicability of these patterns, and their relationship to Alzheimer disease (AD) pathology, in brains of a population-based donor cohort. METHODS: Brains donated in two of six Cognitive Function and Ageing Study ... [Abstract] [Full-text] Dementia and survival in Parkinson disease: a 12-year population study. Neurology, 70(13): 1017-22. BACKGROUND: The risk for dementia in Parkinson disease (PD) is high, with important clinical consequences for patients with PD. However, the absolute risk of dementia and how it affects survival in PD are not known. Such questions are important for patients, their families, and service providers but require long-term studies. METHODS: This study is a prospective longitudinal cohort study with patients from a prevalence study of PD in Norway. Patients were reassessed 4, 8, 9, 10, 11, and 12 ... [Abstract] [Full-text] Articles on Parkinson's Disease published 20 March 2008: Patterns of bidirectional communication between cortex and basal ganglia during movement in patients with Parkinson disease. J Neurosci, 28(12): 3008-16. Cortico-basal ganglia networks are considered to comprise several parallel and mostly segregated loops, where segregation is achieved in space through topographic connectivity. Recently, it has been suggested that functional segregation may also be achieved in the frequency domain, by selective coupling of related activities at different frequencies. So far, however, any coupling across frequency in the human has only been modeled in terms of unidirectional influences, a misplaced assumption ... [Abstract] [Full-text] Articles on Parkinson's Disease published 19 March 2008: Neurotrophic factors as a therapeutic target for Parkinson's disease. Expert Opin Ther Targets, 12(4): 437-47. BACKGROUND: The search for therapeutic agents that might alter the disease course in Parkinson's disease (PD) is ongoing. One area of particular interest involves neurotrophic factors (NTFs), with those of the glial cell line-derived neurotrophic factor (GDNF) family showing greatest promise. The safety and efficacy of these therapies has recently come into question. Furthermore, many of the key questions pertaining to such therapies, such as the optimal method of delivery, timing of treatment ... [Abstract] [Full-text] Potential therapeutic targets for Parkinson's disease. Expert Opin Ther Targets, 12(4): 425-36. BACKGROUND: Parkinson's disease is a common disorder that becomes more prevalent with advanced age. The cardinal features are related to dopamine deficiency, arising from loss of neurons projecting from the substantia nigra in the midbrain to the striatum. Therapies based on dopamine replacement are well established but while highly effective, leave a number of currently unmet needs. These include features of disease that are probably not related to dopamine deficiency and are unresponsive to ... [Abstract] [Full-text] Exploring gene-environment interactions in Parkinson's disease. Hum Genet, 123(3): 257-65. The objective of this study was to explore combined effects of four candidate susceptibility genes and two exposures on Parkinson's disease (PD) risk; namely, alpha-synuclein (SNCA) promoter polymorphism REP1, microtubule-associated protein tau (MAPT) H1/H2 haplotypes, apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 polymorphism, ubiquitin carboxy-terminal esterase L1 (UCHL1) S18Y variant, cigarette smoking and caffeinated coffee consumption. 932 PD patients and 664 control subjects from the ... [Abstract] [Full-text] Articles on Parkinson's Disease published 17 March 2008: A case report on fixation instability in Parkinson's disease with bilateral deep brain stimulation implants. J Neurol Neurosurg Psychiatry, 79(4): 443-7. We report on fixation instabilities in a patient diagnosed with Parkinson's disease (PD). This patient underwent deep brain stimulation (DBS) surgery bilaterally in the vicinity of the subthalamic nuclei (STN). Examination of the eye movements of this patient revealed marked fixation instability compared with a healthy age matched control. The eye movements occurring during fixation differed from other reports of fixation instabilities in that they interrupted fixation for only brief durations. ... [Abstract] [Full-text] © 2004-2008 Parkinson's Disease Research Today. All Rights Reserved. |
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