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See detailThe Luxembourg Parkinson’s Study: A Comprehensive Approach for Stratification and Early Diagnosis
Hipp Epouse D'amico, Géraldine UL; Vaillant, Michel; Diederich, Nico J. et al

in Frontiers in Aging Neuroscience (2018), 10

While genetic advances have successfully defined part of the complexity in Parkinson’s disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies ... [more ▼]

While genetic advances have successfully defined part of the complexity in Parkinson’s disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies typically include patients with earlier disease stages and exclude comorbidities, thus ignoring a substantial part of the real-world PD population. To account for these limitations, we implemented the Luxembourg PD study as a comprehensive clinical, molecular and device-based approach including patients with typical PD and atypical parkinsonism, irrespective of their disease stage, age, comorbidities, or linguistic background. To provide a large, longitudinally followed, and deeply phenotyped set of patients and controls for clinical and fundamental research on PD, we implemented an open-source digital platform that can be harmonized with international PD cohort studies. Our interests also reflect Luxembourg-specific areas of PD research, including vision, gait, and cognition. This effort is flanked by comprehensive biosampling efforts assuring high quality and sustained availability of body liquids and tissue biopsies. We provide evidence for the feasibility of such a cohort program with deep phenotyping and high quality biosampling on parkinsonism in an environment with structural specificities and alert the international research community to our willingness to collaborate with other centers. The combination of advanced clinical phenotyping approaches including device-based assessment will create a comprehensive assessment of the disease and its variants, its interaction with comorbidities and its progression. We envision the Luxembourg Parkinson’s study as an important research platform for defining early diagnosis and progression markers that translate into stratified treatment approaches. [less ▲]

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See detailMetformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
Fitzgerald, Julia C.; Zimprich, Alexander; Carvajal-Berrio, Daniel A. et al

in Brain : A Journal of Neurology (2017), 140(9), 2444-2459

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 ... [more ▼]

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HtrA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HtrA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HtrA2 and PINK1. HtrA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HtrA2 protease activity. Following genetic screening of Parkinson’s disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson’s disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HtrA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson’s disease and provide new prospects for targeted therapies. [less ▲]

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See detailNeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases
Blauwendraat, Cornelis; Faghri, Faraz; Pihlstrom, Lasse et al

in Neurobiology of Aging (2017)

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina ... [more ▼]

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array, and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases. [less ▲]

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See detailEvaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study.
Wang, Lisa; Heckman, Michael G.; Aasly, Jan O. et al

in Neurobiology of aging (2017), 49

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed ... [more ▼]

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. [less ▲]

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See detailGenome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?
Lohmann, Katja; Schmidt, Alexander; Schillert, Arne et al

in Movement disorders : official journal of the Movement Disorder Society (2014), 29(7), 921-7

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument ... [more ▼]

Musician's dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writer's dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2-stage genome-wide association study in whites. Genotypes at 557,620 single-nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10(-5) and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome-wide significant SNP (P < 5 x 10(-8) ) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 x 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 x 10(-2) ) but not with any other focal or segmental dystonia. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (lambda = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients. [less ▲]

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See detailEIF4G1 is neither a strong nor a common risk factor for Parkinson's disease: evidence from large European cohorts
Huttenlocher, Johanna; Krüger, Rejko UL; Capetian, Philipp et al

in Journal of medical genetics (2014), 0

BACKGROUND: Missense mutations in the eukaryotic translation initiation factor 4-gamma 1 (EIF4G1) gene have previously been implicated in familial Parkinson's disease (PD). A large PD family with ... [more ▼]

BACKGROUND: Missense mutations in the eukaryotic translation initiation factor 4-gamma 1 (EIF4G1) gene have previously been implicated in familial Parkinson's disease (PD). A large PD family with autosomal-dominant segregation showed a heterozygous missense mutation and additional patients were found to have unique sequence variants that have not been observed in controls. Subsequent studies have reported contradictory findings. METHODS: We assessed the relevance of EIF4G1 mutations in a European cohort of 2146 PD patients. Of these, 2051 sporadic PD patients were screened for the reported p.Ala502Val and p.Arg1205His mutations. In addition, the complete coding region of EIF4G1 was directly sequenced in 95 familial PD patients with autosomal-dominant inheritance. Moreover, we imputed the p.Arg1205His substitution and tested for association with PD in the Icelandic population (93 698 samples). RESULTS: We did not observe the presence of the p.Ala502Val substitution in our cohort; however, the p.Arg1205His mutation was identified in one sporadic PD patient. The same mutation was also found in 76 Icelandic subjects older than 65 years using haplotype imputing. Only five of these subjects reported PD symptoms (OR 1.3, p=0.50). Thus, if causal, the p.Arg1205His EIF4G1 mutation has a low penetrance or a late onset manifestation. A novel variant p.Arg566Cys found in a patient with familial PD did not cosegregate with PD in all three affected siblings. All further recently published EIF4G1 mutations found in our cohort are likely to be benign polymorphisms. CONCLUSIONS: This is the largest genetic study of EIF4G1 mutations in PD. Our data do not support the EIF4G1 gene as a high-risk PD locus, neither for the familial nor the sporadic condition. Furthermore, the p.Arg1205His mutation is not significantly associated with increased risk of PD in the Icelandic population. Therefore, caution should be exercised when interpreting EIF4G1 genotyping results in isolated patients and PD families. In summary, diagnostic testing of EIF4G1 should not be recommended in clinical settings. [less ▲]

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See detailFrom genome-wide association studies to next-generation sequencing: lessons from the past and planning for the future.
Sharma, Manu; Krüger, Rejko UL; Gasser, Thomas

in JAMA neurology (2014), 71(1), 5-6

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See detailGenetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression.
Reinhardt, Peter; Schmid, Benjamin; Burbulla, Lena F. et al

in Cell Stem Cell (2013), 12(3), 354-67

The LRRK2 mutation G2019S is the most common genetic cause of Parkinson's disease (PD). To better understand the link between mutant LRRK2 and PD pathology, we derived induced pluripotent stem cells from ... [more ▼]

The LRRK2 mutation G2019S is the most common genetic cause of Parkinson's disease (PD). To better understand the link between mutant LRRK2 and PD pathology, we derived induced pluripotent stem cells from PD patients harboring LRRK2 G2019S and then specifically corrected the mutant LRRK2 allele. We demonstrate that gene correction resulted in phenotypic rescue in differentiated neurons and uncovered expression changes associated with LRRK2 G2019S. We found that LRRK2 G2019S induced dysregulation of CPNE8, MAP7, UHRF2, ANXA1, and CADPS2. Knockdown experiments demonstrated that four of these genes contribute to dopaminergic neurodegeneration. LRRK2 G2019S induced increased extracellular-signal-regulated kinase 1/2 (ERK) phosphorylation. Transcriptional dysregulation of CADPS2, CPNE8, and UHRF2 was dependent on ERK activity. We show that multiple PD-associated phenotypes were ameliorated by inhibition of ERK. Therefore, our results provide mechanistic insight into the pathogenesis induced by mutant LRRK2 and pointers for the development of potential new therapeutics. [less ▲]

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See detailDerivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling.
Reinhardt, Peter; Glatza, Michael; Hemmer, Kathrin et al

in PLoS ONE (2013), 8(3), 59252

Phenotypic drug discovery requires billions of cells for high-throughput screening (HTS) campaigns. Because up to several million different small molecules will be tested in a single HTS campaign, even ... [more ▼]

Phenotypic drug discovery requires billions of cells for high-throughput screening (HTS) campaigns. Because up to several million different small molecules will be tested in a single HTS campaign, even small variability within the cell populations for screening could easily invalidate an entire campaign. Neurodegenerative assays are particularly challenging because neurons are post-mitotic and cannot be expanded for implementation in HTS. Therefore, HTS for neuroprotective compounds requires a cell type that is robustly expandable and able to differentiate into all of the neuronal subtypes involved in disease pathogenesis. Here, we report the derivation and propagation using only small molecules of human neural progenitor cells (small molecule neural precursor cells; smNPCs). smNPCs are robust, exhibit immortal expansion, and do not require cumbersome manual culture and selection steps. We demonstrate that smNPCs have the potential to clonally and efficiently differentiate into neural tube lineages, including motor neurons (MNs) and midbrain dopaminergic neurons (mDANs) as well as neural crest lineages, including peripheral neurons and mesenchymal cells. These properties are so far only matched by pluripotent stem cells. Finally, to demonstrate the usefulness of smNPCs we show that mDANs differentiated from smNPCs with LRRK2 G2019S are more susceptible to apoptosis in the presence of oxidative stress compared to wild-type. Therefore, smNPCs are a powerful biological tool with properties that are optimal for large-scale disease modeling, phenotypic screening, and studies of early human development. [less ▲]

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See detailLRRK2: Understanding the role of common and rare variants in Parkinson's disease.
Sharma, Manu; Krüger, Rejko UL; Gasser, Thomas

in Movement disorders : official journal of the Movement Disorder Society (2012), 27(4), 475

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See detailDeep-brain-stimulation does not impair deglutition in Parkinson's disease.
Lengerer, Sabrina; Kipping, Judy; Rommel, Natalie et al

in Parkinsonism & related disorders (2012), 18(7), 847-53

OBJECTIVE: A large proportion of patients with Parkinson's disease develop dysphagia during the course of the disease. Dysphagia in Parkinson's disease affects different phases of deglutition, has a ... [more ▼]

OBJECTIVE: A large proportion of patients with Parkinson's disease develop dysphagia during the course of the disease. Dysphagia in Parkinson's disease affects different phases of deglutition, has a strong impact on quality of life and may cause severe complications, i.e., aspirational pneumonia. So far, little is known on how deep-brain-stimulation of the subthalamic nucleus influences deglutition in PD. METHODS: Videofluoroscopic swallowing studies on 18 patients with Parkinson's disease, which had been performed preoperatively, and postoperatively with deep-brain-stimulation-on and deep-brain-stimulation-off, were analyzed retrospectively. The patients were examined in each condition with three consistencies (viscous, fluid and solid). The 'New Zealand index for multidisciplinary evaluation of swallowing (NZIMES) Subscale One' for qualitative and 'Logemann-MBS-Parameters' for quantitative evaluation were assessed. RESULTS: Preoperatively, none of the patients presented with clinically relevant signs of dysphagia. While postoperatively, the mean daily levodopa equivalent dosage was reduced by 50% and deep-brain-stimulation led to a 50% improvement in motor symptoms measured by the UPDRS III, no clinically relevant influence of deep-brain-stimulation-on swallowing was observed using qualitative parameters (NZIMES). However quantitative parameters (Logemann scale) found significant changes of pharyngeal parameters with deep-brain-stimulation-on as compared to preoperative condition and deep-brain-stimulation-off mostly with fluid consistency. CONCLUSION: In Parkinson patients without dysphagia deep-brain-stimulation of the subthalamic nucleus modulates the pharyngeal deglutition phase but has no clinically relevant influence on deglutition. Further studies are needed to test if deep-brain-stimulation is a therapeutic option for patients with swallowing disorders. [less ▲]

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See detailA multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.
Sharma, Manu; Ioannidis, John P. A.; Aasly, Jan O. et al

in Journal of medical genetics (2012), 49(11), 721-6

BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense ... [more ▼]

BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide. [less ▲]

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See detailLong-term follow-up of subthalamic nucleus stimulation in glucocerebrosidase-associated Parkinson's disease.
Weiss, Daniel; Brockmann, Kathrin; Srulijes, Karin et al

in Journal of neurology (2012), 259(9), 1970-2

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See detailLarge-scale replication and heterogeneity in Parkinson disease genetic loci.
Sharma, Manu; Ioannidis, John P. A.; Aasly, Jan O. et al

in Neurology (2012), 79(7), 659-67

OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The ... [more ▼]

OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. [less ▲]

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See detailRole of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease.
Sharma, Manu; Maraganore, Demetrius M.; Ioannidis, John P. A. et al

in Neurobiology of aging (2011), 32(11), 21081-5

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for ... [more ▼]

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3' untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I(2) Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies. [less ▲]

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See detailA large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease.
Krüger, Rejko UL; Sharma, Manu; Riess, Olaf et al

in Neurobiology of aging (2011), 32(3), 5489-18

High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the ... [more ▼]

High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide. [less ▲]

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See detailPeriphilin is a novel interactor of synphilin-1, a protein implicated in Parkinson's disease.
Soehn, Anne S.; Franck, Thomas; Biskup, Saskia et al

in Neurogenetics (2010), 11(2), 203-15

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein and its interactor synphilin-1 are major ... [more ▼]

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein and its interactor synphilin-1 are major components of these inclusions. Rare mutations in the alpha-synuclein and synphilin-1 genes have been implicated in the pathogenesis of PD; however, the normal function of these proteins is far from being completely elucidated. We, thus, searched for novel synphilin-1-interacting proteins and deciphered periphilin as new interactor. Periphilin isoforms are involved in multiple cellular functions in vivo, and the protein is broadly expressed during embryogenesis and in the adult brain. We show that periphilin displays an overlapping expression pattern with synphilin-1 in cellular and animal models and in Lewy bodies of PD patients. Functional studies demonstrate that periphilin, as previously shown for synphilin-1, displays an antiapoptotic function by reducing caspase-3 activity. Searching for mutations in the periphilin gene, we detected a K69E substitution in two patients of a PD family. Taken together, these findings support for the first time an involvement of periphilin in PD. [less ▲]

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See detailInvoluntary eyelid closure after STN-DBS: evidence for different pathophysiological entities.
Weiss, Daniel; Wachter, Tobias; Breit, Sorin et al

in Journal of neurology, neurosurgery, and psychiatry (2010), 81(9), 1002-7

OBJECTIVE: Involuntary eyelid closure (IEC) may occur after deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson's disease (PD) and is often categorised as apraxia of lid opening (ALO ... [more ▼]

OBJECTIVE: Involuntary eyelid closure (IEC) may occur after deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson's disease (PD) and is often categorised as apraxia of lid opening (ALO), albeit the appropriateness of this term is under debate. To gain insight into the hitherto undefined pathophysiology of IEC after STN-DBS, we performed a comprehensive clinical and electrophysiological characterisation of lid function in a total of six PD patients. METHODS: The study was carried out in six PD patients who developed IEC after STN-DBS. They underwent neurological examination and electromyography recording of activity in the orbicularis oculi muscle (OO) upon varying stimulation patterns. Intraoperative studies were performed in one patient. RESULTS: Increasing STN-DBS intensity induced IEC in four patients, whereas it improved the condition in two. Needle EMG showed tonic hyperactivity of the OO in STN-DBS induced IEC, while variable patterns of OO activity (irregular and tonic) were seen in patients with STN-DBS-relieved IEC. Intraoperative analysis in one patient showed evidence for IEC being induced by activation of corticobulbar fibres. CONCLUSIONS: We identified two groups of IEC after STN-DBS based on clinical and EMG patterns: (1) STN-DBS induced IEC associated with tonic OO overactivity and (2) STN-DBS relieved IEC presenting with variable EMG patterns. Our findings provide relevant information on pathophysiology of STN-DBS related IEC and implications for its therapeutic management. [less ▲]

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See detailSevere muscular fasciculations as an uncommon side-effect due to microdefect of an extension wire in deep brain stimulation.
Wachter, Tobias; Weiss, Daniel; Breit, Sorin et al

in Movement disorders : official journal of the Movement Disorder Society (2009), 24(14), 2161-2

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See detailFurther delineation of the association signal on chromosome 5 from the first whole genome association study in Parkinson's disease.
Sharma, Manu; Lichtner, Peter; Krüger, Rejko UL et al

in Neurobiology of aging (2009), 30(10), 1706-9

A recently published whole genome association study showed the involvement of 13 SNPs in the pathogenesis of Parkinson disease (PD). We performed a replication study to assess their involvement in our ... [more ▼]

A recently published whole genome association study showed the involvement of 13 SNPs in the pathogenesis of Parkinson disease (PD). We performed a replication study to assess their involvement in our sporadic cohort consisting of 663 cases and 1002 controls ascertained from Germany. One of the previously reported SNP, rs7723605, showed evidence of association (p value 0.04) in our sample. We further refined the signal by genotyping additional 22 SNPs around SNP rs7723605. Our refinement analysis, however, did not provide evidence for association in our sample after adjusting for multiple testing by permutation procedure. In conclusion, our study did not lend support to the finding that the reported SNPs are directly influencing the susceptibility to sporadic form of PD at least in our population. [less ▲]

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