References of "Krüger, Rejko 50002143"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailEvaluating the Use of Circulating MicroRNA Profiles for Lung Cancer Detection in Symptomatic Patients
Fehlmann, Tobias; Kahraman, Mustafa; Backes, Christina et al

in JAMA Oncology (2020)

Importance The overall low survival rate of patients with lung cancer calls for improved detection tools to enable better treatment options and improved patient outcomes. Multivariable molecular ... [more ▼]

Importance The overall low survival rate of patients with lung cancer calls for improved detection tools to enable better treatment options and improved patient outcomes. Multivariable molecular signatures, such as blood-borne microRNA (miRNA) signatures, may have high rates of sensitivity and specificity but require additional studies with large cohorts and standardized measurements to confirm the generalizability of miRNA signatures. Objective To investigate the use of blood-borne miRNAs as potential circulating markers for detecting lung cancer in an extended cohort of symptomatic patients and control participants. Design, Setting, and Participants This multicenter, cohort study included patients from case-control and cohort studies (TREND and COSYCONET) with 3102 patients being enrolled by convenience sampling between March 3, 2009, and March 19, 2018. For the cohort study TREND, population sampling was performed. Clinical diagnoses were obtained for 3046 patients (606 patients with non–small cell and small cell lung cancer, 593 patients with nontumor lung diseases, 883 patients with diseases not affecting the lung, and 964 unaffected control participants). No samples were removed because of experimental issues. The collected data were analyzed between April 2018 and November 2019. Main Outcomes and Measures Sensitivity and specificity of liquid biopsy using miRNA signatures for detection of lung cancer. Results A total of 3102 patients with a mean (SD) age of 61.1 (16.2) years were enrolled. Data on the sex of the participants were available for 2856 participants; 1727 (60.5%) were men. Genome-wide miRNA profiles of blood samples from 3046 individuals were evaluated by machine-learning methods. Three classification scenarios were investigated by splitting the samples equally into training and validation sets. First, a 15-miRNA signature from the training set was used to distinguish patients diagnosed with lung cancer from all other individuals in the validation set with an accuracy of 91.4% (95% CI, 91.0%-91.9%), a sensitivity of 82.8% (95% CI, 81.5%-84.1%), and a specificity of 93.5% (95% CI, 93.2%-93.8%). Second, a 14-miRNA signature from the training set was used to distinguish patients with lung cancer from patients with nontumor lung diseases in the validation set with an accuracy of 92.5% (95% CI, 92.1%-92.9%), sensitivity of 96.4% (95% CI, 95.9%-96.9%), and specificity of 88.6% (95% CI, 88.1%-89.2%). Third, a 14-miRNA signature from the training set was used to distinguish patients with early-stage lung cancer from all individuals without lung cancer in the validation set with an accuracy of 95.9% (95% CI, 95.7%-96.2%), sensitivity of 76.3% (95% CI, 74.5%-78.0%), and specificity of 97.5% (95% CI, 97.2%-97.7%). Conclusions and Relevance The findings of the study suggest that the identified patterns of miRNAs may be used as a component of a minimally invasive lung cancer test, complementing imaging, sputum cytology, and biopsy tests. [less ▲]

Detailed reference viewed: 58 (2 UL)
Full Text
Peer Reviewed
See detailExcess of singleton loss-of-function variants in Parkinson's disease contributes to genetic risk.
Bobbili, Dheeraj Reddy; Banda, Peter UL; Krüger, Rejko UL et al

in Journal of Medical Genetics (2020)

Background Parkinson’s disease (PD) is a neurodegenerative disorder with complex genetic architecture. Besides rare mutations in high-risk genes related to monogenic familial forms of PD, multiple ... [more ▼]

Background Parkinson’s disease (PD) is a neurodegenerative disorder with complex genetic architecture. Besides rare mutations in high-risk genes related to monogenic familial forms of PD, multiple variants associated with sporadic PD were discovered via association studies. Methods We studied the whole-exome sequencing data of 340 PD cases and 146 ethnically matched controls from the Parkinson’s Progression Markers Initiative (PPMI) and performed burden analysis for different rare variant classes. Disease prediction models were built based on clinical, non-clinical and genetic features, including both common and rare variants, and two machine learning methods. Results We observed a significant exome-wide burden of singleton loss-of-function variants (corrected p=0.037). Overall, no exome-wide burden of rare amino acid changing variants was detected. Finally, we built a disease prediction model combining singleton loss-of-function variants, a polygenic risk score based on common variants, and family history of PD as features and reached an area under the curve of 0.703 (95% CI 0.698 to 0.708). By incorporating a rare variant feature, our model increased the performance of the state-of-the-art classification model for the PPMI dataset, which reached an area under the curve of 0.639 based on common variants alone. Conclusion The main finding of this study is to highlight the contribution of singleton loss-of-function variants to the complex genetics of PD and that disease risk prediction models combining singleton and common variants can improve models built solely on common variants. [less ▲]

Detailed reference viewed: 80 (3 UL)
Full Text
Peer Reviewed
See detailFibroblast mitochondria in idiopathic Parkinson’s disease display morphological changes and enhanced resistance to depolarization
Krüger, Rejko UL; Balling, Rudolf UL; Antony, Paul UL et al

in Scientific Reports (2020)

Mitochondrial dysfunction is a hallmark in idiopathic Parkinson’s disease (IPD). Here, we established screenable phenotypes of mitochondrial morphology and function in primary fibroblasts derived from ... [more ▼]

Mitochondrial dysfunction is a hallmark in idiopathic Parkinson’s disease (IPD). Here, we established screenable phenotypes of mitochondrial morphology and function in primary fibroblasts derived from patients with IPD. Upper arm punch skin biopsy was performed in 41 patients with mid-stage IPD and 21 age-matched healthy controls. At the single-cell level, the basal mitochondrial membrane potential (Ψm) was higher in patients with IPD than in controls. Similarly, under carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) stress, the remaining Ψm was increased in patients with IPD. Analysis of mitochondrial morphometric parameters revealed significantly decreased mitochondrial connectivity in patients with IPD, with 9 of 14 morphometric mitochondrial parameters differing from those in controls. Significant morphometric mitochondrial changes included the node degree, mean volume, skeleton size, perimeter, form factor, node count, erosion body count, endpoints, and mitochondria count (all P-values < 0.05). These functional data reveal that resistance to depolarization was increased by treatment with the protonophore FCCP in patients with IPD, whereas morphometric data revealed decreased mitochondrial connectivity and increased mitochondrial fragmentation. [less ▲]

Detailed reference viewed: 115 (5 UL)
Full Text
Peer Reviewed
See detailUnraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia
Krüger, Rejko UL; Cheng, Fubo; Walter, Michael et al

in Journal of Molecular Neuroscience (2020)

Mutations in THAP1 (THAP domain-containing apoptosis-associated protein 1) are responsible for DYT6 dystonia. Until now, more than eighty differentmutations in THAP1 gene have been found in patientswith ... [more ▼]

Mutations in THAP1 (THAP domain-containing apoptosis-associated protein 1) are responsible for DYT6 dystonia. Until now, more than eighty differentmutations in THAP1 gene have been found in patientswith primary dystonia, and two third of them are missense mutations. The potential pathogeneses of these missense mutations in human are largely elusive. In the present study, we generated stable transfected human neuronal cell lines expressing wild-type or mutated THAP1 proteins found in DYT6 patients. Transcriptional profiling using microarrays revealed a set of 28 common genes dysregulated in two mutated THAP1 (S21T and F81L) overexpression cell lines suggesting a common mechanism of these mutations. ChIP-seq showed that THAP1 can bind to the promoter of one of these genes, superoxide dismutase 2 (SOD2). Overexpression of THAP1 in SK-N-AS cells resulted in increased SOD2 protein expression, whereas fibroblasts from THAP1 patients have less SOD2 expression, which indicates that SOD2 is a direct target gene of THAP1. In addition, we show that some THAP1 mutations (C54Y and F81L) decrease the protein stability which might also be responsible for altered transcription regulation due to dosage insufficiency. Taking together, the current study showed different potential pathogenic mechanisms of THAP1 mutations which lead to the same consequence of DYT6 dystonia. [less ▲]

Detailed reference viewed: 103 (0 UL)
Full Text
Peer Reviewed
See detailUsing High-Content Screening to Generate Single-Cell Gene-Corrected Patient-Derived iPS Clones Reveals Excess Alpha-Synuclein with Familial Parkinson's Disease Point Mutation A30P.
Barbuti, Peter UL; Antony, Paul UL; Rodrigues Santos, Bruno UL et al

in Cells (2020), 9(9),

The generation of isogenic induced pluripotent stem cell (iPSC) lines using CRISPR-Cas9 technology is a technically challenging, time-consuming process with variable efficiency. Here we use fluorescence ... [more ▼]

The generation of isogenic induced pluripotent stem cell (iPSC) lines using CRISPR-Cas9 technology is a technically challenging, time-consuming process with variable efficiency. Here we use fluorescence-activated cell sorting (FACS) to sort biallelic CRISPR-Cas9 edited single-cell iPSC clones into high-throughput 96-well microtiter plates. We used high-content screening (HCS) technology and generated an in-house developed algorithm to select the correctly edited isogenic clones for continued expansion and validation. In our model we have gene-corrected the iPSCs of a Parkinson's disease (PD) patient carrying the autosomal dominantly inherited heterozygous c.88G>C mutation in the SNCA gene, which leads to the pathogenic p.A30P form of the alpha-synuclein protein. Undertaking a PCR restriction-digest mediated clonal selection strategy prior to sequencing, we were able to post-sort validate each isogenic clone using a quadruple screening strategy prior to generating footprint-free isogenic iPSC lines, retaining a normal molecular karyotype, pluripotency and three germ-layer differentiation potential. Directed differentiation into midbrain dopaminergic neurons revealed that SNCA expression is reduced in the gene-corrected clones, which was validated by a reduction at the alpha-synuclein protein level. The generation of single-cell isogenic clones facilitates new insights in the role of alpha-synuclein in PD and furthermore is applicable across patient-derived disease models. [less ▲]

Detailed reference viewed: 88 (1 UL)
Full Text
Peer Reviewed
See detailDie Geschichte des ‚Freezing-of-gait‘ beim Parkinson-Syndrom – vom Phänomen zum Symptom.
Klucken, Jochen; Winkler, Juergen; Krüger, Rejko UL et al

in Fortschritte der Neurologie-Psychiatrie (2020), 88(9), 573-581

The background of the freezing-of-gait (FOG) phenomenon in Parkinson's syndrome is presented in this review. The following issues are addressed: characterization of the symptom freezing and its subtypes ... [more ▼]

The background of the freezing-of-gait (FOG) phenomenon in Parkinson's syndrome is presented in this review. The following issues are addressed: characterization of the symptom freezing and its subtypes that challenge standardized diagnostic procedures; available assessment methods generating freezing-related parameters that not only support clinical studies but can also be applied in everyday care, and current therapy options. FOG exists in different subtypes, and clinical and diagnostic definitions are limited by subjective characterization and semi-standardized tests. FOG-specific drug options are not existing, apart from the optimization of dopaminergic medication, which may also be due to the poor discriminatory power of standardized diagnostics. This is also true for deep brain stimulation. Both of these therapeutic options may be due not only to the complex neural network alterations as a motor-control correlate of FOG, but also because of challenging diagnostic assessments methodologies. Innovative, wearable, sensor-based diagnostic strategies are currently being developed, and supportive therapies using tools and technologies focusing on 'cueing' are becoming increasingly well accepted. Even though high level evidence is missing, they provide a helpful treatment option for individualized therapy. It can be assumed that these options will become particularly popular due to technological progress and likely alter the everyday treatment challenges faced by doctors and therapists. [less ▲]

Detailed reference viewed: 19 (0 UL)
Full Text
Peer Reviewed
See detailThe atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides.
Meyrath, Max; Szpakowska, Martyna; Zeiner, Julian et al

in Nature communications (2020), 11(1), 3033

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7 ... [more ▼]

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity. [less ▲]

Detailed reference viewed: 72 (0 UL)
Full Text
Peer Reviewed
See detailHuman Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors.
Bus, Christine; Zizmare, Laimdota; Feldkaemper, Marita et al

in iScience (2020), 23(12), 101797

PINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated. Here, the ... [more ▼]

PINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated. Here, the absence of PINK1 in human dopaminergic neurons inhibits ionophore-induced mitophagy and reduces mitochondrial membrane potential. Compensatory, mitochondrial renewal maintains mitochondrial morphology and protects the respiratory chain. This is paralleled by metabolic changes, including inhibition of the TCA cycle enzyme mAconitase, accumulation of NAD(+), and metabolite depletion. Loss of PINK1 disrupts dopamine metabolism by critically affecting its synthesis and uptake. The mechanism involves steering of key amino acids toward energy production rather than neurotransmitter metabolism and involves cofactors related to the vitamin B6 salvage pathway identified using unbiased multi-omics approaches. We propose that reduction of mitochondrial membrane potential that cannot be controlled by PINK1 signaling initiates metabolic compensation that has neurometabolic consequences relevant to Parkinson disease. [less ▲]

Detailed reference viewed: 61 (2 UL)
Full Text
Peer Reviewed
See detailContributing Factors and Evolution of Impulse Control Disorder in the Luxembourg Parkinson Cohort.
Binck, Sylvia UL; Pauly, Claire UL; Vaillant, Michel et al

in Frontiers in neurology (2020), 11

Background: To establish the frequency of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Within the Luxembourg Parkinson's Study, PD patients were evaluated for ICD presence (score ≥ ... [more ▼]

Background: To establish the frequency of impulse control disorder (ICD) in Parkinson's disease (PD). Methods: Within the Luxembourg Parkinson's Study, PD patients were evaluated for ICD presence (score ≥ 1 on MDS-UPDRS I item 1.6), use of dopamine agonists (DA) and other medications. Results: 470 patients were enrolled. Among 217 patients without DA use, 6.9% scored positive for ICD, vs. 15.4% among 253 patients with DA use (p = 0.005). The regression analysis showed that age at PD diagnosis had only a minor impact on ICD occurrence, while there was no influence by gender or co-medications. The longitudinal study over 2 years in 156 patients demonstrated increasing ICD frequency in DA users (p = 0.005). Conclusion: This large and non-interventional study confirms that PD patients with DA treatment show higher frequency of ICD than patients without DA use. It newly demonstrates that ICD can develop independently from age, gender, or co-medications. [less ▲]

Detailed reference viewed: 30 (0 UL)
Full Text
Peer Reviewed
See detailMachine learning-assisted neurotoxicity prediction in human midbrain organoids
Monzel, Anna Sophia UL; Hemmer, K; Smits, Lisa UL et al

in Parkinsonism and Related Disorders (2020)

Detailed reference viewed: 60 (6 UL)
Full Text
Peer Reviewed
See detailA patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.
Boussaad, Ibrahim UL; Obermaier, Carolin D.; Hanss, Zoé et al

in Science translational medicine (2020), 12(560),

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic ... [more ▼]

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD. [less ▲]

Detailed reference viewed: 123 (6 UL)
Full Text
Peer Reviewed
See detailThe Emerging Role of RHOT1/Miro1 in the Pathogenesis of Parkinson's Disease.
Grossmann, Dajana; Berenguer-Escuder, Clara; Chemla, Axel UL et al

in Frontiers in neurology (2020), 11

The expected increase in prevalence of Parkinson's disease (PD) as the most common neurodegenerative movement disorder over the next years underscores the need for a better understanding of the underlying ... [more ▼]

The expected increase in prevalence of Parkinson's disease (PD) as the most common neurodegenerative movement disorder over the next years underscores the need for a better understanding of the underlying molecular pathogenesis. Here, first insights provided by genetics over the last two decades, such as dysfunction of molecular and organellar quality control, are described. The mechanisms involved relate to impaired intracellular calcium homeostasis and mitochondrial dynamics, which are tightly linked to the cross talk between the endoplasmic reticulum (ER) and mitochondria. A number of proteins related to monogenic forms of PD have been mapped to these pathways, i.e., PINK1, Parkin, LRRK2, and α-synuclein. Recently, Miro1 was identified as an important player, as several studies linked Miro1 to mitochondrial quality control by PINK1/Parkin-mediated mitophagy and mitochondrial transport. Moreover, Miro1 is an important regulator of mitochondria-ER contact sites (MERCs), where it acts as a sensor for cytosolic calcium levels. The involvement of Miro1 in the pathogenesis of PD was recently confirmed by genetic evidence based on the first PD patients with heterozygous mutations in RHOT1/Miro1. Patient-based cellular models from RHOT1/Miro1 mutation carriers showed impaired calcium homeostasis, structural alterations of MERCs, and increased mitochondrial clearance. To account for the emerging role of Miro1, we present a comprehensive overview focusing on the role of this protein in PD-related neurodegeneration and highlighting new developments in our understanding of Miro1, which provide new avenues for neuroprotective therapies for PD patients. [less ▲]

Detailed reference viewed: 15 (3 UL)
Full Text
Peer Reviewed
See detailImpaired Mitochondrial-Endoplasmic Reticulum Interaction and Mitophagy in Miro1-Mutant Neurons in Parkinson’s Disease
Berenguer-Escuder, Clara; Grossmann, Dajana; Antony, Paul UL et al

in Human Molecular Genetics (2020)

Detailed reference viewed: 311 (13 UL)
Full Text
Peer Reviewed
See detailVariants in Miro1 cause alterations of ER-mitochondria contact sites in fibroblasts from Parkinson's disease patients
Berenguer, Clara UL; Grossmann, Dajana; Massart, François UL et al

in Journal of Clinical Medicine (2019)

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD ... [more ▼]

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD‐associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial‐endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient‐derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration. [less ▲]

Detailed reference viewed: 97 (11 UL)
Full Text
Peer Reviewed
See detailGene-environment interaction and Mendelian randomisation
Krüger, Rejko UL; Kolber, Pierre Luc UL

in Revue Neurologique (2019)

Genetic factors only account for up to a third of the cases of Parkinson's disease (PD), while the remaining cases are of unknown aetiology. Environmental exposures (such as pesticides or heavy metals ... [more ▼]

Genetic factors only account for up to a third of the cases of Parkinson's disease (PD), while the remaining cases are of unknown aetiology. Environmental exposures (such as pesticides or heavy metals) and the interaction with genetic susceptibility factors (summarized in the concept of impaired xenobiotic metabolism) are believed to play a major role in the mechanisms of neurodegeneration. Beside of the classical association studies (e.g. genome-wide association studies), a novel approach to investigate environmental risk factors are Mendelian randomisation studies. This review explores the gene-environment interaction and the gain of Mendelian randomisation studies in assessing causalities of modifiable risk factors for PD. [less ▲]

Detailed reference viewed: 45 (0 UL)
Full Text
Peer Reviewed
See detailMultilingual Validation of the First French Version of Munich Dysphagia Test-Parkinson's Disease (MDT-PD) in the Luxembourg Parkinson's Study
Simons, Janine UL; Vaillant, Michel; Hipp Epouse D'amico, Géraldine UL et al

in Frontiers in Neurology (2019)

The Munich Dysphagia Test for Parkinson's disease (MDT-PD) was initially developed and validated in the German population as a highly sensitive and specific self-reported screening questionnaire to detect ... [more ▼]

The Munich Dysphagia Test for Parkinson's disease (MDT-PD) was initially developed and validated in the German population as a highly sensitive and specific self-reported screening questionnaire to detect early oropharyngeal symptoms and aspiration risk in patients with idiopathic Parkinson's disease (iPD). In order to make this tool accessible for prevention in the French speaking populations worldwide, we performed the first French translation and provide a linguistic and psychometric validation in the unique multilingual environment of the Luxembourg Parkinson's Study. [less ▲]

Detailed reference viewed: 36 (1 UL)
Full Text
Peer Reviewed
See detailConnecting environmental exposure and neurodegeneration using cheminformatics and high resolution mass spectrometry: potential and challenges
Schymanski, Emma UL; Baker, Nancy C.; Williams, Antony J et al

in Environmental Science. Processes and Impacts (2019)

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary ... [more ▼]

Connecting chemical exposures over a lifetime to complex chronic diseases with multifactorial causes such as neurodegenerative diseases is an immense challenge requiring a long-term, interdisciplinary approach. Rapid developments in analytical and data technologies, such as non-target high resolution mass spectrometry (NT-HR-MS), have opened up new possibilities to accomplish this, inconceivable 20 years ago. While NT-HR-MS is being applied to increasingly complex research questions, there are still many unidentified chemicals and uncertainties in linking exposures to human health outcomes and environmental impacts. In this perspective, we explore the possibilities and challenges involved in using cheminformatics and NT-HR-MS to answer complex questions that cross many scientific disciplines, taking the identification of potential (small molecule) neurotoxicants in environmental or biological matrices as a case study. We explore capturing literature knowledge and patient exposure information in a form amenable to high-throughput data mining, and the related cheminformatic challenges. We then briefly cover which sample matrices are available, which method(s) could potentially be used to detect these chemicals in various matrices and what remains beyond the reach of NT-HR-MS. We touch on the potential for biological validation systems to contribute to mechanistic understanding of observations and explore which sampling and data archiving strategies may be required to form an accurate, sustained picture of small molecule signatures on extensive cohorts of patients with chronic neurodegenerative disorders. Finally, we reflect on how NT-HR-MS can support unravelling the contribution of the environment to complex diseases. [less ▲]

Detailed reference viewed: 77 (9 UL)
Full Text
Peer Reviewed
See detailDeep Brain Stimulation for Freezing of Gait in Parkinson’s Disease With Early Motor Complications
Krüger, Rejko UL; EARLYSTIM study group; Barbe, Michael

in Movement Disorders (2019)

Background: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. Objective: Secondary analysis to assess whether DBS affects these symptoms within a large randomized ... [more ▼]

Background: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. Objective: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIMtrial). [less ▲]

Detailed reference viewed: 88 (3 UL)
Full Text
Peer Reviewed
See detailMutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.
Grossmann, Dajana UL; Berenguer, Clara UL; Bellet, Marie Estelle et al

in Antioxidants & redox signaling (2019)

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial ... [more ▼]

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition (MiST), which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in RHOT1 have been identified. RESULTS: Here, for the first time, we describe heterozygous RHOT1 mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient-derived cellular models. Both mutations lead to decreased ER-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn lead to increased mitophagy. CONCLUSION: In summary, our data support the role of Miro1 in maintaining calcium homeostasis and mitochondrial quality control in PD. [less ▲]

Detailed reference viewed: 297 (36 UL)
Full Text
Peer Reviewed
See detailAutomated high-throughput high-content autophagy and mitophagy analysis platform
Arias, Jonathan UL; Jarazo, Javier UL; Walter, Jonas UL et al

in Scientific Reports (2019)

Autophagic processes play a central role in cellular homeostasis. In pathological conditions, the flow of autophagy can be affected at multiple and distinct steps of the pathway. Current analyses tools do ... [more ▼]

Autophagic processes play a central role in cellular homeostasis. In pathological conditions, the flow of autophagy can be affected at multiple and distinct steps of the pathway. Current analyses tools do not deliver the required detail for dissecting pathway intermediates. The development of new tools to analyze autophagic processes qualitatively and quantitatively in a more straightforward manner is required. Defining all autophagy pathway intermediates in a high-throughput manner is technologically challenging and has not been addressed yet. Here, we overcome those requirements and limitations by the developed of stable autophagy and mitophagy reporter-iPSC and the establishment of a novel high-throughput phenotyping platform utilizing automated high-content image analysis to assess autophagy and mitophagy pathway intermediates. [less ▲]

Detailed reference viewed: 181 (28 UL)