Mosaicism of alpha-synuclein gene rearrangements: Report of two unrelated cases of early-onset parkinsonism

Dear Sir, In genetics, the term ‘mosaicism’ describes the situation in which groups of cells have a different genetic composition to other cells in an organism. Somatic gene rearrangements due to multiplication or deletion of genes (copy number variation) and/or sections of chromosomes can lead to mosaicism. The presence of multiple copies of the alpha-synuclein gene (SNCA) is known to be associated with Parkinson’s disease (PD) and the severity of symptoms increases with the number of copies of the gene [1]. While the features of PD associated with duplication of SNCA are usually (but not always) typical of the condition [2–3], patients with triplicate copies have atypical features, including rapidly evolving symptoms, severe cognitive impairment, limited response to levodopa, more severe symptoms of dementia and more..

Hypothesis: Somatic Mosaicism and Parkinson Disease

Letter to the EditorFil: Perandones, Carlos Edgardo. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Pellene, L. A. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Giugni, J. C.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Calvo, D. S.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Raina, G. B.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Cuevas, S. M.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Mata, I. F.. University of Washington; Estados UnidosFil: Zabetian, C. P.. University of Washington; Estados UnidosFil: Caputo, Mariela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Corach, Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; ArgentinaFil: Micheli, Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; ArgentinaFil: Radrizzani Helguera, Martin. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease

DJ-1 is a multifunctional protein that plays an important role in oxidative stress, cell death, and synucleinopathies, including Parkinson disease. Previous studies have demonstrated that total DJ-1 levels decrease in the cerebrospinal fluid, but do not change significantly in human plasma from patients with Parkinson disease when compared with controls. In this study, we measured total DJ-1 and its isoforms in whole blood of patients with Parkinson disease at various stages, Alzheimer disease, and healthy controls to identify potential peripheral biomarkers of PD. In an initial discovery study of 119 subjects, 7 DJ-1 isoforms were reliably detected, and blood levels of those with 4-hydroxy-2-nonenal modifications were discovered to be altered in late-stage Parkinson disease. This result was further confirmed in a validation study of another 114 participants, suggesting that, unlike total DJ-1 levels, post-translationally modified isoforms of DJ-1 from whole blood are candidate biomarkers of late-stage Parkinson disease

Role of MAPT mutations and haplotype in frontotemporal lobar degeneration in Northern Finland

<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) consists of a clinically and neuropathologically heterogeneous group of syndromes affecting the frontal and temporal lobes of the brain. Mutations in microtubule-associated protein tau (<it>MAPT</it>), progranulin (<it>PGRN</it>) and charged multi-vesicular body protein 2B (<it>CHMP2B</it>) are associated with familial forms of the disease. The prevalence of these mutations varies between populations. The H1 haplotype of <it>MAPT </it>has been found to be closely associated with tauopathies and with sporadic FTLD. Our aim was to investigate <it>MAPT </it>mutations and haplotype frequencies in a clinical series of patients with FTLD in Northern Finland.</p> <p>Methods</p> <p><it>MAPT </it>exons 1, 2 and 9–13 were sequenced in 59 patients with FTLD, and <it>MAPT </it>haplotypes were analysed in these patients, 122 patients with early onset Alzheimer's disease (eoAD) and 198 healthy controls.</p> <p>Results</p> <p>No pathogenic mutations were found. The H2 allele frequency was 11.0% (<it>P </it>= 0.028) in the FTLD patients, 9.8% (<it>P </it>= 0.029) in the eoAD patients and 5.3% in the controls. The H2 allele was especially clustered in patients with a positive family history (<it>P </it>= 0.011) but did not lower the age at onset of the disease. The ApoE4 allele frequency was significantly increased in the patients with eoAD and in those with FTLD.</p> <p>Conclusion</p> <p>We conclude that although pathogenic <it>MAPT </it>mutations are rare in Northern Finland, the <it>MAPT </it>H2 allele may be associated with increased risks of FTLD and eoAD in the Finnish population.</p

Letter to the Editor: Hypothesis: Somatic Mosaicism and Parkinson Disease

Fil: Perandones, Claudia. ANLIS Dr.C.G.Malbrán. Dirección Científico Técnica; Argentina.Fil: Pellene, Luis A. Universidad Nacional de Buenos Aires. Hospital de Clínicas. Programa de Parkinson y Movimientos Anormales; Argentina.Fil: Giugni, J. C. Universidad Nacional de Buenos Aires. Hospital de Clínicas. Programa de Parkinson y Movimientos Anormales; Argentina.Fil: Calvo, D. S. Universidad Nacional de Buenos Aires. Hospital de Clínicas. Programa de Parkinson y Movimientos Anormales; Argentina.Fil: Raina, G. B. Universidad Nacional de Buenos Aires. Hospital de Clínicas. Programa de Parkinson y Movimientos Anormales; Argentina.Fil: Cuevas, S. M. Universidad Nacional de Buenos Aires. Hospital de Clínicas. Programa de Parkinson y Movimientos Anormales; Argentina.Fil: Mata, Ignacio F. University of Washington and VA Puget Sound Health Care System, Seattle, Washington; Estados Unidos.Fil: Zabetian, Cyrus P. University of Washington and VA Puget Sound Health Care System, Seattle, Washington; Estados Unidos.Fil: Caputo, Mariela. Universidad de Buenos Aires. Escuela de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina.Fil: Corach, Daniel. Universidad de Buenos Aires. Escuela de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina.Fil: Micheli, Federico E. Universidad Nacional de Buenos Aires. Hospital de Clínicas. Programa de Parkinson y Movimientos Anormales; Argentina.Fil: Radrizzani, Martin. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología. Centro de Estudios en Salud y Medio Ambiente. Laboratorio de Citogenética Neuro y Molecular; Argentina

Neuropathological and Genetic Correlates of Survival and Dementia Onset in Synucleinopathies: A Retrospective Analysis

Background Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer\u27s disease pathology according to US National Institute on Aging–Alzheimer\u27s Association neuropathological criteria, and used multivariate regression to control for age at death and sex. Findings On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer\u27s disease neuropathology, 56 (26%) with low-level Alzheimer\u27s disease neuropathology, 45 (21%) with intermediate-level Alzheimer\u27s disease neuropathology, and 63 (30%) with high-level Alzheimer\u27s disease neuropathology. As levels of Alzheimer\u27s disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p \u3c 0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β −4·0, 95% CI −5·5 to −2·6; p \u3c 0·0001; R 2 0·22, p \u3c 0·0001) and with survival (–2·0, −3·2 to −0·8; 0·003; 0·15, \u3c 0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation Alzheimer\u27s disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer\u27s disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer\u27s disease neuropathology

Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in CSF of healthy volunteers

BACKGROUND: Concentrations of monoamine metabolites in human cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. CSF monoamine metabolite concentrations are partly determined by genetic influences. METHODS: We investigated possible relationships between DNA polymorphisms in the serotonin 2C receptor (HTR2C), the serotonin 3A receptor (HTR3A), the dopamine D(4 )receptor (DRD4), and the dopamine β-hydroxylase (DBH) genes and CSF concentrations of 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 90). RESULTS: The HTR3A 178 C/T variant was associated with 5-HIAA levels (p = 0.02). The DBH-1021 heterozygote genotype was associated with 5-HIAA (p = 0.0005) and HVA (p = 0.009) concentrations. Neither the HTR2C Cys23Ser variant, nor the DRD4 -521 C/T variant were significantly associated with any of the monoamine metabolites. CONCLUSIONS: The present results suggest that the HTR3A and DBH genes may participate in the regulation of dopamine and serotonin turnover rates in the central nervous system

Prevalence of Metabolic Syndrome in Iranian Professional Drivers: Results from a Population Based Study of 12,138 Men

It is evident that professional driving is associated with substantial changes in lifestyle habits. Professional drivers are prone to metabolic syndrome (MetS) and its complications because their working environment is characterized by numerous stress factors such as lack of physical activity due to working in a fixed position, disruption in diet, and irregular sleep habits. The aim of the present study was to estimate the prevalence of MetS among long distance drivers residing in West Azerbaijan province in Iran.To assess the prevalence of metabolic syndrome among professional long distance drivers, 12138 participants were enrolled in this cross sectional study. The MetS was defined using International Diabetes Federation criteria.Among12138 participants, 3697 subjects found to be MetS. The crude and age-adjusted rates of MetS were 30.5% and 32.4% respectively. Based on Body mass index (BMI), 5027 subjects (41.4%) were overweight (BMI ≥25.01–30 kg/m2), and 2592 (21.3%) were obese (BMI ≥30.01 kg/m2). The presence of central obesity was more common than other components. The associations of MetS with BMI, pack-year smoking, age, weekly driving duration and driving experiences were significant in the logistic regression. By increasing BMI, pack-year smoking, age, weekly driving duration and driving experiences, odds ratio of MetS was increased.The study suggests that MetS has become a noteworthy health problem among Iranian long distance drivers. This might be due to the following facts: sitting in a fixed position for long hours while working, cigarette smoking, job stress, unhealthy diet and lack of physical activity. Educational programs should be established for promoting healthy lifestyle and also for early detection and appropriate intervention

LRRK2 at the interface of autophagosomes, endosomes and lysosomes

Over the past 20 years, substantial progress has been made in identifying the underlying genetics of Parkinson’s disease (PD). Of the known genes, LRRK2 is a major genetic contributor to PD. However, the exact function of LRRK2 remains to be elucidated. In this review, we discuss how familial forms of PD have led us to hypothesize that alterations in endomembrane trafficking play a role in the pathobiology of PD. We will discuss the major observations that have been made to elucidate the role of LRRK2 in particular, including LRRK2 animal models and high-throughput proteomics approaches. Taken together, these studies strongly support a role of LRRK2 in vesicular dynamics. We also propose that targeting these pathways may not only be beneficial for developing therapeutics for LRRK2-driven PD, but also for other familial and sporadic cases

Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ∼27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P<5×10−8) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3×10−8). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies