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See detailMitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1.
Burbulla, L. F.; Fitzgerald, J. C.; Stegen, K. et al

in Cell death & disease (2014), 5

The mitochondrial chaperone mortalin was implicated in Parkinson's disease (PD) because of its reduced levels in the brains of PD patients and disease-associated rare genetic variants that failed to ... [more ▼]

The mitochondrial chaperone mortalin was implicated in Parkinson's disease (PD) because of its reduced levels in the brains of PD patients and disease-associated rare genetic variants that failed to rescue impaired mitochondrial integrity in cellular knockdown models. To uncover the molecular mechanisms underlying mortalin-related neurodegeneration, we dissected the cellular surveillance mechanisms related to mitochondrial quality control, defined the effects of reduced mortalin function at the molecular and cellular levels and investigated the functional interaction of mortalin with Parkin and PINK1, two PD-related proteins involved in mitochondrial homeostasis. We found that reduced mortalin function leads to: (1) activation of the mitochondrial unfolded protein response (UPR(mt)), (2) increased susceptibility towards intramitochondrial proteolytic stress, (3) increased autophagic degradation of fragmented mitochondria and (4) reduced mitochondrial mass in human cells in vitro and ex vivo. These alterations caused increased vulnerability toward apoptotic cell death. Proteotoxic perturbations induced by either partial loss of mortalin or chemical induction were rescued by complementation with native mortalin, but not disease-associated mortalin variants, and were independent of the integrity of autophagic pathways. However, Parkin and PINK1 rescued loss of mortalin phenotypes via increased lysosomal-mediated mitochondrial clearance and required intact autophagic machinery. Our results on loss of mortalin function reveal a direct link between impaired mitochondrial proteostasis, UPR(mt) and PD and show that effective removal of dysfunctional mitochondria via either genetic (PINK1 and Parkin overexpression) or pharmacological intervention (rapamycin) may compensate mitochondrial phenotypes. [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 detailAlpha-synuclein repeat variants and survival in Parkinson's disease.
Chung, Sun Ju; Biernacka, Joanna M.; Armasu, Sebastian M. et al

in Movement disorders : official journal of the Movement Disorder Society (2014)

OBJECTIVES: To determine whether alpha-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). METHODS: Investigators from the Genetic Epidemiology of ... [more ▼]

OBJECTIVES: To determine whether alpha-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. RESULTS: Twenty-one sites contributed data for 6,154 cases. There was no significant association between alpha-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). CONCLUSIONS: In our large consortium study, alpha-synuclein REP1 genotypes were not associated with survival in PD. Further studies of alpha-synuclein's role in disease progression and long-term outcomes are needed. (c) 2014 International Parkinson and Movement Disorder Society. [less ▲]

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See detailThe hallmarks of Parkinson's disease.
Antony, Paul UL; Diederich, Nico UL; Krüger, Rejko UL et al

in FEBS Journal (2013)

Since the discovery of dopamine as a neurotransmitter in the 1950s, Parkinson's disease (PD) research has generated a rich and complex body of knowledge, revealing PD to be an age-related multifactorial ... [more ▼]

Since the discovery of dopamine as a neurotransmitter in the 1950s, Parkinson's disease (PD) research has generated a rich and complex body of knowledge, revealing PD to be an age-related multifactorial disease, influenced by both genetic and environmental factors. The tremendous complexity of the disease is increased by a non-linear progression of the pathogenesis between molecular, cellular, and organic systems. In this mini-review, we explore the complexity of PD and propose a systems-based approach, organizing the available information around cellular disease hallmarks. We encourage our peers to adopt this cell-based view with the aim of improving communication in interdisciplinary research endeavors targeting the molecular events, modulatory cell-to-cell signaling pathways, and emerging clinical phenotypes related to PD. This article is protected by copyright. All rights reserved. [less ▲]

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See detailKnockdown of Hsc70-5/mortalin induces loss of synaptic mitochondria in a Drosophila Parkinson's disease model.
Zhu, Jun-Yi; Vereshchagina, Natalia; Sreekumar, Vrinda et al

in PloS one (2013), 8(12), 83714

Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of ... [more ▼]

Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson's disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism. [less ▲]

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See detailNovel SLC9A6 mutations in two families with Christianson syndrome.
Riess, A.; Rossier, E.; Krüger, Rejko UL et al

in Clinical genetics (2013), 83(6), 596-7

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See detailEffects of transcranial direct current stimulation (tDCS) on executive functions: influence of COMT Val/Met polymorphism.
Plewnia, Christian; Zwissler, Bastian; Langst, Isabella et al

in Cortex : A Journal Devoted to the Study of the Nervous System & Behavior (2013), 49(7), 1801-7

INTRODUCTION: Transcranial direct current stimulation (tDCS) is a frequently used technique to investigate healthy and impaired neuronal functions. Its modulatory effect on executive functions is of ... [more ▼]

INTRODUCTION: Transcranial direct current stimulation (tDCS) is a frequently used technique to investigate healthy and impaired neuronal functions. Its modulatory effect on executive functions is of particular interest for understanding the mechanisms underlying integration of cognition and behavior. The key role of prefrontal dopamine function for executive functions suggest that differences of the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene would interact with tDCS interventions in this domain. In this study, we hypothesized that the COMT Met allele homozygosity, associated with higher levels of prefrontal dopamine, would influence the effect of tDCS on higher-level executive functions. METHOD: Forty-six healthy subjects participated in a double-blind sham-controlled crossover study and underwent COMT genotyping. Anodal tDCS (20 min, 1 mA) to the left dorsolateral prefrontal cortex (dlPFC) or sham stimulation was applied during the performance of a parametric Go/No-Go (PGNG) test measuring sustained attention, response inhibition and cognitive flexibility as measured by set-shifting. RESULTS: In COMT Met/Met allele carrier anodal tDCS of the dlPFC was associated with a deterioration of set-shifting ability, which is assessed by the most challenging level of the PGNG. Without regard to the carrier status of the COMT Val158Met polymorphism no effects of anodal tDCS on executive functions could be determined. CONCLUSIONS: In line with the model of non-linear effects of l-dopa on cortical plasticity high dopaminergic prefrontal activity mediated by COMT Val158Met polymorphism predicts a detrimental effect of anodal tDCS on cognitive flexibility. Therefore, we suggest that the individual genetic profile may modulate behavioral effect of tDCS. More precise application of brain stimulation techniques according to the individual genetic patterns may support the development of personalized treatment approaches. [less ▲]

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See detailDe novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).
Karle, Kathrin N.; Biskup, Saskia; Schule, Rebecca et al

in Neurology (2013), 81(23), 2039-44

OBJECTIVE: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is ... [more ▼]

OBJECTIVE: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years. METHODS: In a continuous series of 25 patients with adult-onset leukoencephalopathy of unknown cause, we genetically confirmed HDLS in 6 families. Affected and nonaffected individuals were examined clinically and by brain MRI studies. RESULTS: HDLS presented as prominent dementia and apraxia, often with extrapyramidal and pyramidal signs, rarely with ataxia. White matter MRI changes were detectable early in the disease course. Family history was negative in 4 of 6 index patients. In 2 of 6 index patients, we could confirm the occurrence of de novo mutations in the CSF1R gene. One family showed possible incomplete penetrance: the 69-year-old father of the index patient carried a CSF1R mutation but was clinically unaffected. In one family, the parents were apparently unaffected and not available for genetic testing. CONCLUSIONS: Typical clinical phenotype and early brain MRI alterations can help to guide the diagnosis of HDLS. Because we confirmed de novo mutations in one-third of patients with CSF1R mutations, this diagnosis should be considered even in the absence of a family history. Furthermore, we present evidence for reduced penetrance of a CSF1R mutation. These results have substantial impact for genetic counseling of asymptomatic individuals at risk and should foster research into disease-modifying factors. [less ▲]

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See detailPopulation-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.
Heckman, Michael G.; Soto-Ortolaza, Alexandra I.; Aasly, Jan O. et al

in Movement disorders : official journal of the Movement Disorder Society (2013), 28(12), 1740-4

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease ... [more ▼]

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. METHODS: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. RESULTS: Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. CONCLUSIONS: Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. [less ▲]

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See detailA novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network.
Grau, Tanja; Burbulla, Lena F.; Engl, Gertraud et al

in Journal of medical genetics (2013), 50(12), 848-58

BACKGROUND: Mutations in OPA3 have been reported in patients with autosomal dominant optic atrophy plus cataract and Costeff syndrome. Here, we report the results of a comprehensive study on OPA3 ... [more ▼]

BACKGROUND: Mutations in OPA3 have been reported in patients with autosomal dominant optic atrophy plus cataract and Costeff syndrome. Here, we report the results of a comprehensive study on OPA3 mutations, including the mutation spectrum and its prevalence in a large cohort of OPA1-negative autosomal dominant optic atrophy (ADOA) patients, the associated clinical phenotype and the functional characterisation of a newly identified OPA3 mutant. METHODS: Mutation analysis was carried out in a patient cohort of 121 independent ADOA patients. To characterise a novel OPA3 mutation, we analysed the mitochondrial import, steady-state levels and the mitochondrial localisation of the mutated protein in patients' fibroblasts. Furthermore, the morphology of mitochondria harbouring the mutated OPA3 was monitored. RESULTS: We identified four independent cases (representing families with multiple affected members) with OPA3 mutations. Besides the known p.Q105E mutation, we observed a novel insertion, c.10_11insCGCCCG/p.V3_G4insAP which is located in the mitochondrial presequence. Detailed functional analysis of mitochondria harbouring this novel mutation demonstrates a fragmented mitochondrial network with a decreased mitochondrial mass in patient fibroblasts. In addition, quantification of the OPA3 protein reveals decreased steady-state levels of the mutant protein compared with the native one. Comparison of the clinical phenotypes suggests that OPA3 mutations can additionally evoke hearing loss and by that extend the clinical manifestation of OPA3-associated optic atrophy. This finding is supported by expression analysis of OPA3 in murine cochlear tissue. CONCLUSIONS: In summary, our study provides new insights into the clinical spectrum and the pathogenesis of dominant optic atrophy caused by mutations in the OPA3 gene. [less ▲]

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See detailNeurostimulation for Parkinson's disease with early motor complications.
Schuepbach, W. M. M.; Rau, J.; Knudsen, K. et al

in The New England journal of medicine (2013), 368(7), 610-22

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We ... [more ▼]

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.). [less ▲]

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See detailNigral stimulation for resistant axial motor impairment in Parkinson's disease? A randomized controlled trial.
Weiss, Daniel; Walach, Margarete; Meisner, Christoph et al

in Brain : a journal of neurology (2013), 136(Pt 7), 2098-108

Gait and balance disturbances typically emerge in advanced Parkinson's disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore ... [more ▼]

Gait and balance disturbances typically emerge in advanced Parkinson's disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 x 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson's Disease Rating Scale score (Scale II items 13-15, Scale III items 27-31) at '3-week follow-up'. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the '3-week follow-up'. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no 'global' effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the substantia nigra pars reticulata possibly improves otherwise resistant freezing of gait and, therefore, highly warrants a subsequent phase III randomized controlled trial. [less ▲]

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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 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 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 detailPhosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function.
Fitzgerald, J. C.; Camprubi, M. D.; Dunn, L. et al

in Cell death and differentiation (2012), 19(2), 257-66

The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that ... [more ▼]

The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that mutations adjacent to two putative phosphorylation sites (S142 and S400) have been found in Parkinson's disease patients. However, the mechanism of this neuroprotection and the signalling pathways associated with it remain mostly unknown. Here we report that cyclin-dependent kinase-5 (Cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating HtrA2 at S400. HtrA2 and Cdk5 interact in human and mouse cell lines and brain, and Cdk5 phosphorylates S400 on HtrA2 in a p38-dependent manner. Phosphorylation of HtrA2 at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring cells protection against cellular stress. [less ▲]

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See detailThe modulation of Amyotrophic Lateral Sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect.
Gispert, Suzana; Kurz, Alexander; Waibel, Stefan et al

in Neurobiology of disease (2012), 45(1), 356-61

Full expansions of the polyglutamine domain (polyQ>/=34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a ... [more ▼]

Full expansions of the polyglutamine domain (polyQ>/=34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27</=polyQ</=33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30</=polyQ</=35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor. [less ▲]

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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 detailGuidelines for the use and interpretation of assays for monitoring autophagy.
Klionsky, Daniel J.; Abdalla, Fabio C.; Abeliovich, Hagai et al

in Autophagy (2012), 8(4), 445-544

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field ... [more ▼]

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field. [less ▲]

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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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