RESUMEN
Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson's disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) human iPSC reporter line, we here generate time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicts novel regulators of mDAN differentiation and super-enhancers are used to identify key TFs. We find LBX1, NHLH1 and NR2F1/2 to promote mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. A more detailed investigation of TF targets reveals that NHLH1 promotes the induction of neuronal miR-124, LBX1 regulates cholesterol biosynthesis, and NR2F1/2 controls neuronal activity.
Asunto(s)
Neuronas Dopaminérgicas , Células Madre Pluripotentes Inducidas , Humanos , Neuronas Dopaminérgicas/metabolismo , Multiómica , Mesencéfalo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Diferenciación Celular/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genéticaRESUMEN
OBJECTIVE: The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration. METHODS: We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case-control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function. RESULTS: Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14-1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18-1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid. INTERPRETATION: OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024;96:133-149.
Asunto(s)
Mitocondrias , Herencia Multifactorial , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Herencia Multifactorial/genética , Mitocondrias/genética , Masculino , Femenino , Fosforilación Oxidativa , Persona de Mediana Edad , Anciano , Estudios de Casos y Controles , Células Madre Pluripotentes Inducidas , Predisposición Genética a la Enfermedad/genética , Puntuación de Riesgo GenéticoRESUMEN
Parkinson's disease (PD) is a complex, progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain. Despite extensive research efforts, the molecular and cellular changes that precede neurodegeneration in PD are poorly understood. To address this, here we describe the use of patient specific human midbrain organoids harboring the SNCA triplication to investigate mechanisms underlying dopaminergic degeneration. Our midbrain organoid model recapitulates key pathological hallmarks of PD, including the aggregation of α-synuclein and the progressive loss of dopaminergic neurons. We found that these pathological hallmarks are associated with an increase in senescence associated cellular phenotypes in astrocytes including nuclear lamina defects, the presence of senescence associated heterochromatin foci, and the upregulation of cell cycle arrest genes. These results suggest a role of pathological α-synuclein in inducing astrosenescence which may, in turn, increase the vulnerability of dopaminergic neurons to degeneration.
Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Astrocitos/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Mesencéfalo/metabolismo , Mesencéfalo/patología , Neuronas Dopaminérgicas/metabolismo , Organoides/metabolismo , Organoides/patología , Sustancia Negra/metabolismoRESUMEN
BACKGROUND: Double-blind studies have demonstrated that motor complications in Parkinson's disease (PD) can be reduced with continuous delivery of levodopa. The DopaFuse system is a novel, intraoral micropump that attaches to a retainer and uses a propellant to deliver levodopa/carbidopa (LD/CD) continuously into the mouth. OBJECTIVES: Evaluate the safety, pharmacokinetics, and efficacy of LD/CD delivered via the DopaFuse system compared to treatment with intermittent doses of standard oral LD/CD in PD patients with motor fluctuations. METHODS: This was a 2-week, open-label study (NCT04778176) in 16 PD patients treated with ≥4 levodopa doses/day and experiencing motor fluctuations. On Day 1 (clinic setting) patients received their usual dose of standard LD/CD; DopaFuse therapy was initiated on Day 2, and on Day 3 patients received DopaFuse plus a morning oral LD/CD dose. Patients returned home on Days 4-14 and returned for in-clinic assessment on Day 15. RESULTS: Continuous DopaFuse delivery of LD/CD was associated with reduced variability in plasma levodopa levels compared to oral LD/CD (mean ± SD levodopa Fluctuation Index reduced from 2.15 ± 0.59 on Day1 to 1.50 ± 0.55 on Day 2 (P = 0.0129) and to 1.03 ± 0.53 on Day 3 (P < 0.0001)). This pharmacokinetic improvement translated into significantly reduced OFF time with DopaFuse therapy (reduction of -1.72 ± 0.37 h at Day 15; P = 0.0004) and increased ON time without severe dyskinesias (increase of 1.72 ± 0.37 h at Day 15; P = 0.0004) versus oral LD/CD administration. DopaFuse therapy was not associated with any clinically significant adverse events. CONCLUSIONS: Continuous delivery of LD/CD using the DopaFuse system was associated with significantly less variability in plasma levodopa concentrations and reductions in OFF time compared to treatment with standard oral LD/CD therapy and was well tolerated. © 2024 International Parkinson and Movement Disorder Society.
Asunto(s)
Antiparkinsonianos , Carbidopa , Levodopa , Enfermedad de Parkinson , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/administración & dosificación , Carbidopa/farmacocinética , Carbidopa/administración & dosificación , Combinación de Medicamentos , Levodopa/farmacocinética , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. OBJECTIVE: The aim of this study was to characterize a novel phosphatase tensin homolog-induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family. METHODS: Exome sequencing of a well-characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. RESULTS: We identified a homozygous chr1:20648535-20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved DFG motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. CONCLUSIONS: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedad de Parkinson , Linaje , Proteínas Quinasas , Humanos , Proteínas Quinasas/genética , Enfermedad de Parkinson/genética , India , Femenino , Masculino , Persona de Mediana Edad , Mutación con Pérdida de Función/genética , Adulto , Ubiquitina-Proteína Ligasas/genética , Mutación/genética , Secuenciación del Exoma , Mitofagia/genéticaRESUMEN
BACKGROUND: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. OBJECTIVES: Our goal was to investigate the effects of genetic variants on risk and time to LID. METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147). CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMEN
Decline in immune function during aging increases susceptibility to different aging-related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here, we show that loss of DJ-1 encoded by PARK7/DJ-1, causing early-onset familial Parkinson's disease (PD), unexpectedly diminished signs of immunoaging in T-cell compartments of both human and mice. Compared with two gender-matched unaffected siblings of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled non-senescent T cells. The observation was further consolidated by the results in 45-week-old DJ-1 knockout mice. Our data demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Mechanistically, DJ-1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T-cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases.
Asunto(s)
Estrés Oxidativo , Enfermedad de Parkinson , Envejecimiento/genética , Animales , Humanos , Ratones , Ratones Noqueados , Estrés Oxidativo/genética , Enfermedad de Parkinson/genética , Proteína Desglicasa DJ-1/genética , Proteína Desglicasa DJ-1/metabolismo , Linfocitos TRESUMEN
INTRODUCTION: While there is an interest in defining longitudinal change in people with chronic illness like Parkinson's disease (PD), statistical analysis of longitudinal data is not straightforward for clinical researchers. Here, we aim to demonstrate how the choice of statistical method may influence research outcomes, (e.g., progression in apathy), specifically the size of longitudinal effect estimates, in a cohort. METHODS: In this retrospective longitudinal analysis of 802 people with typical Parkinson's disease in the Luxembourg Parkinson's study, we compared the mean apathy scores at visit 1 and visit 8 by means of the paired two-sided t-test. Additionally, we analysed the relationship between the visit numbers and the apathy score using linear regression and longitudinal two-level mixed effects models. RESULTS: Mixed effects models were the only method able to detect progression of apathy over time. While the effects estimated for the group comparison and the linear regression were smaller with high p-values (+ 1.016/ 7 years, p = 0.107, -0.056/ 7 years, p = 0.897, respectively), effect estimates for the mixed effects models were positive with a very small p-value, indicating a significant increase in apathy symptoms by + 2.345/ 7 years (p < 0.001). CONCLUSION: The inappropriate use of paired t-tests and linear regression to analyse longitudinal data can lead to underpowered analyses and an underestimation of longitudinal change. While mixed effects models are not without limitations and need to be altered to model the time sequence between the exposure and the outcome, they are worth considering for longitudinal data analyses. In case this is not possible, limitations of the analytical approach need to be discussed and taken into account in the interpretation.
Asunto(s)
Apatía , Progresión de la Enfermedad , Enfermedad de Parkinson , Humanos , Apatía/fisiología , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/diagnóstico , Masculino , Femenino , Estudios Longitudinales , Modelos Lineales , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Modelos EstadísticosRESUMEN
BACKGROUND: During the COVID-19 pandemic swift implementation of research cohorts was key. While many studies focused exclusively on infected individuals, population based cohorts are essential for the follow-up of SARS-CoV-2 impact on public health. Here we present the CON-VINCE cohort, estimate the point and period prevalence of the SARS-CoV-2 infection, reflect on the spread within the Luxembourgish population, examine immune responses to SARS-CoV-2 infection and vaccination, and ascertain the impact of the pandemic on population psychological wellbeing at a nationwide level. METHODS: A representative sample of the adult Luxembourgish population was enrolled. The cohort was followed-up for twelve months. SARS-CoV-2 RT-qPCR and serology were conducted at each sampling visit. The surveys included detailed epidemiological, clinical, socio-economic, and psychological data. RESULTS: One thousand eight hundred sixty-five individuals were followed over seven visits (April 2020-June 2021) with the final weighted period prevalence of SARS-CoV-2 infection of 15%. The participants had similar risks of being infected regardless of their gender, age, employment status and education level. Vaccination increased the chances of IgG-S positivity in infected individuals. Depression, anxiety, loneliness and stress levels increased at a point of study when there were strict containment measures, returning to baseline afterwards. CONCLUSION: The data collected in CON-VINCE study allowed obtaining insights into the infection spread in Luxembourg, immunity build-up and the impact of the pandemic on psychological wellbeing of the population. Moreover, the study holds great translational potential, as samples stored at the biobank, together with self-reported questionnaire information, can be exploited in further research. TRIAL REGISTRATION: Trial registration number: NCT04379297, 10 April 2020.
Asunto(s)
COVID-19 , Adulto , Humanos , COVID-19/epidemiología , SARS-CoV-2 , Pandemias , Luxemburgo/epidemiología , Ansiedad/epidemiologíaRESUMEN
Wearable sensors could be beneficial for the continuous quantification of upper limb motor symptoms in people with Parkinson's disease (PD). This work evaluates the use of two inertial measurement units combined with supervised machine learning models to classify and predict a subset of MDS-UPDRS III subitems in PD. We attached the two compact wearable sensors on the dorsal part of each hand of 33 people with PD and 12 controls. Each participant performed six clinical movement tasks in parallel with an assessment of the MDS-UPDRS III. Random forest (RF) models were trained on the sensor data and motor scores. An overall accuracy of 94% was achieved in classifying the movement tasks. When employed for classifying the motor scores, the averaged area under the receiver operating characteristic values ranged from 68% to 92%. Motor scores were additionally predicted using an RF regression model. In a comparative analysis, trained support vector machine models outperformed the RF models for specific tasks. Furthermore, our results surpass the literature in certain cases. The methods developed in this work serve as a base for future studies, where home-based assessments of pharmacological effects on motor function could complement regular clinical assessments.
Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico , Aprendizaje Automático , Movimiento , Aprendizaje Automático Supervisado , ManoRESUMEN
BACKGROUND: Astrocytes have recently gained attention as key contributors to the pathogenesis of neurodegenerative disorders including Parkinson's disease. To investigate human astrocytes in vitro, numerous differentiation protocols have been developed. However, the properties of the resulting glia are inconsistent, which complicates the selection of an appropriate method for a given research question. Thus, we compared two approaches for the generation of iPSC-derived astrocytes. We phenotyped glia that were obtained employing a widely used long, serum-free ("LSF") method against an in-house established short, serum-containing ("SSC") protocol which allows for the generation of astrocytes and midbrain neurons from the same precursor cells. RESULTS: We employed high-content confocal imaging and RNA sequencing to characterize the cultures. The astrocytes generated with the LSF or SSC protocols differed considerably in their properties: while the former cells were more labor-intense in their generation (5 vs 2 months), they were also more mature. This notion was strengthened by data resulting from cell type deconvolution analysis that was applied to bulk transcriptomes from the cultures to assess their similarity with human postmortem astrocytes. CONCLUSIONS: Overall, our analyses highlight the need to consider the advantages and disadvantages of a given differentiation protocol, when designing functional or drug discovery studies involving iPSC-derived astrocytes.
RESUMEN
BACKGROUND: In the older general population, neurodegenerative diseases (NDs) are associated with increased disability, decreased physical and cognitive function. Detecting risk factors can help implement prevention measures. Using deep neural networks (DNNs), a machine-learning algorithm could be an alternative to Cox regression in tabular datasets with many predictive features. We aimed to compare the performance of different types of DNNs with regularized Cox proportional hazards models to predict NDs in the older general population. METHODS: We performed a longitudinal analysis with participants of the English Longitudinal Study of Ageing. We included men and women with no NDs at baseline, aged 60 years and older, assessed every 2 years from 2004 to 2005 (wave2) to 2016-2017 (wave 8). The features were a set of 91 epidemiological and clinical baseline variables. The outcome was new events of Parkinson's, Alzheimer or dementia. After applying multiple imputations, we trained three DNN algorithms: Feedforward, TabTransformer, and Dense Convolutional (Densenet). In addition, we trained two algorithms based on Cox models: Elastic Net regularization (CoxEn) and selected features (CoxSf). RESULTS: 5433 participants were included in wave 2. During follow-up, 12.7% participants developed NDs. Although the five models predicted NDs events, the discriminative ability was superior using TabTransformer (Uno's C-statistic (coefficient (95% confidence intervals)) 0.757 (0.702, 0.805). TabTransformer showed superior time-dependent balanced accuracy (0.834 (0.779, 0.889)) and specificity (0.855 (0.0.773, 0.909)) than the other models. With the CoxSf (hazard ratio (95% confidence intervals)), age (10.0 (6.9, 14.7)), poor hearing (1.3 (1.1, 1.5)) and weight loss 1.3 (1.1, 1.6)) were associated with a higher DNN risk. In contrast, executive function (0.3 (0.2, 0.6)), memory (0, 0, 0.1)), increased gait speed (0.2, (0.1, 0.4)), vigorous physical activity (0.7, 0.6, 0.9)) and higher BMI (0.4 (0.2, 0.8)) were associated with a lower DNN risk. CONCLUSION: TabTransformer is promising for prediction of NDs with heterogeneous tabular datasets with numerous features. Moreover, it can handle censored data. However, Cox models perform well and are easier to interpret than DNNs. Therefore, they are still a good choice for NDs.
Asunto(s)
Enfermedades Neurodegenerativas , Masculino , Humanos , Femenino , Persona de Mediana Edad , Anciano , Estudios de Cohortes , Estudios Longitudinales , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/epidemiología , Aprendizaje Automático , Redes Neurales de la ComputaciónRESUMEN
DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients' frontal cortex, THAP1 patients' induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.
Asunto(s)
Distonía , Trastornos Distónicos , Neuroblastoma , Humanos , Ratones , Animales , Ratas , Distonía/genética , Proteínas Nucleares/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Trastornos Distónicos/genética , Mutación/genética , Factor de Transcripción Sp1/genéticaRESUMEN
INTRODUCTION: Patients with advanced Parkinson disease (PD) often experience problems with mobility, including walking under single- (ST) and dual-tasking (DT) conditions. The effects of deep brain stimulation in the subthalamic nucleus (DBS) versus dopaminergic medication (Med) on these conditions are not well investigated. MATERIALS AND METHODS: We used two ST and two DT-gait paradigms to evaluate the effect of DBS and dopaminergic medication on gait parameters in 14 PD patients (mean age 66 ± 8 years) under DBSOFF/MedON, DBSON/MedOFF, and DBSON/MedON conditions. They performed standardized 20-meter walks with convenient and fast speed. To test DT capabilities, they performed a checking-boxes and a subtraction task during fast-paced walking. Quantitative gait analysis was performed using a tri-axial accelerometer (Dynaport, McRoberts, The Netherlands). Dual-task costs (DTC) of gait parameters and secondary task performance were compared intraindividually between DBSOFF/MedON vs DBSON/MedON, and DBSON/MedOFF vs DBSON/MedON to estimate responsiveness. RESULTS: Dopaminergic medication increased gait speed and cadence at convenient speed. It increased cadence and decreased number of steps at fast speed, and improved DTC of cadence during the checking boxes and DTC of cadence and number of steps during the subtraction tasks. DBS only improved DTC of cadence during the checking boxes and DTC of gait speed during the subtraction task. CONCLUSION: Dopaminergic medication showed larger additional effects on temporal gait parameters under ST and DT conditions in advanced PD than DBS. These results, after confirmation in independent studies, should be considered in the medical management of advanced PD patients with gait and DT deficits.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Persona de Mediana Edad , Anciano , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/complicaciones , Estimulación Encefálica Profunda/métodos , Marcha/fisiología , Caminata/fisiología , Núcleo Subtalámico/fisiologíaRESUMEN
SARS-CoV-2 infection and/or vaccination elicit a broad range of neutralizing antibody responses against the different variants of concern (VOC). We established a new variant-adapted surrogate virus neutralization test (sVNT) and assessed the neutralization activity against the ancestral B.1 (WT) and VOC Delta, Omicron BA.1, BA.2, and BA.5. Analytical performances were compared against the respective VOC to the reference virus neutralization test (VNT) and two CE-IVD labeled kits using three different cohorts collected during the COVID-19 waves. Correlation analyses showed moderate to strong correlation for Omicron sub-variants (Spearman's r = 0.7081 for BA.1, r = 0.7205 for BA.2, and r = 0.6042 for BA.5), and for WT (r = 0.8458) and Delta-sVNT (r = 0.8158), respectively. Comparison of the WT-sVNT performance with two CE-IVD kits, the "Icosagen SARS-CoV-2 Neutralizing Antibody ELISA kit" and the "Genscript cPass, kit" revealed an overall good correlation ranging from 0.8673 to -0.8773 and a midway profile between both commercial kits with 87.76% sensitivity and 90.48% clinical specificity. The BA.2-sVNT performance was similar to the BA.2 Genscript test. Finally, a correlation analysis revealed a strong association (r = 0.8583) between BA.5-sVNT and VNT sVNT using a double-vaccinated cohort (n = 100) and an Omicron-breakthrough infection cohort (n = 91). In conclusion, the sVNT allows for the efficient prediction of immune protection against the various VOCs.
Asunto(s)
Anticuerpos Neutralizantes , COVID-19 , Humanos , Pruebas de Neutralización , SARS-CoV-2 , Infección Irruptiva , Anticuerpos AntiviralesRESUMEN
Mitochondrial Rho GTPase 1 (Miro1) protein is a well-known adaptor for mitochondrial transport and also regulates mitochondrial quality control and function. Furthermore, Miro1 was associated with mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs), which are key regulators of cellular calcium homeostasis and the initiation of autophagy. Impairments of these mechanisms were linked to neurodegeneration in Parkinson's disease (PD). We recently revealed that PD fibroblasts harboring Miro1 mutations displayed dysregulations in MERC organization and abundance, affecting mitochondrial homeostasis and clearance. We hypothesize that mutant Miro1 impairs the function of MERCs and mitochondrial dynamics, altering neuronal homeostasis and integrity in PD. PD skin fibroblasts harboring the Miro1-R272Q mutation were differentiated into patient-derived neurons. Live-cell imaging and immunocytochemistry were used to study mitophagy and the organization and function of MERCs. Markers of autophagy or mitochondrial function were assessed by western blotting. Quantification of organelle juxtapositions revealed an increased number of MERCs in patient-derived neurons. Live-cell imaging results showed alterations of mitochondrial dynamics and increased sensitivity to calcium stress, as well as reduced mitochondrial clearance. Finally, western blot analysis indicated a blockage of the autophagy flux in Miro1-mutant neurons. Miro1-mutant neurons display altered ER-mitochondrial tethering compared with control neurons. This alteration likely interferes with proper MERC function, contributing to a defective autophagic flux and cytosolic calcium handling capacity. Moreover, mutant Miro1 affects mitochondrial dynamics in neurons, which may result in disrupted mitochondrial turnover and altered mitochondrial movement.
Asunto(s)
Retículo Endoplásmico/genética , Mitocondrias/genética , Proteínas Mitocondriales/genética , Enfermedad de Parkinson/genética , Proteínas de Unión al GTP rho/genética , Calcio/metabolismo , Diferenciación Celular/genética , Citosol/metabolismo , Homeostasis/genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Dinámicas Mitocondriales/genética , Mitofagia/genética , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patologíaRESUMEN
BACKGROUND: The etiology of Parkinson's disease (PD) is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy are sufficient to cause PD. OBJECTIVES: We sought to evaluate the difference between controls' and PINK1 patients' derived neurons in their transition from neuroepithelial stem cells to neurons, allowing us to identify potential pathways to target with repurposed compounds. METHODS: Using two-dimensional and three-dimensional models of patients' derived neurons we recapitulated PD-related phenotypes. We introduced the usage of midbrain organoids for testing compounds. Using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), we corrected the point mutations of three patients' derived cells. We evaluated the effect of the selected compound in a mouse model. RESULTS: PD patient-derived cells presented differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to tyrosine hydroxylase positive (TH+) neurons compared to controls' cells. Correction of a patient's point mutation ameliorated the metabolic properties and neuronal firing rates as well as reversing the differentiation phenotype, and reducing the increased astrocytic levels. Treatment with 2-hydroxypropyl-ß-cyclodextrin increased the autophagy and mitophagy capacity of neurons concomitant with an improved dopaminergic differentiation of patient-specific neurons in midbrain organoids and ameliorated neurotoxicity in a mouse model. CONCLUSION: We show that treatment with a repurposed compound is sufficient for restoring the impaired dopaminergic differentiation of PD patient-derived cells. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedad de Parkinson , 2-Hidroxipropil-beta-Ciclodextrina/metabolismo , Animales , Encéfalo/metabolismo , Neuronas Dopaminérgicas/metabolismo , Humanos , Ratones , Neuronas/metabolismo , Organoides/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , FenotipoRESUMEN
Given the clear role of GBA in the pathogenesis of Parkinson's disease (PD) and its impact on phenotypical characteristics, this review provides an overview of the current knowledge of GBA-associated PD with a special focus on clinical trajectories and the underlying pathological mechanisms. Importantly, differences and characteristics based on mutation severity are recognized, and current as well as potential future treatment options are discussed. These findings will inform future strategies for patient stratification and cohort enrichment as well as suitable outcome measures when designing clinical trials.
Asunto(s)
Enfermedad de Parkinson , Estudios de Cohortes , Glucosilceramidasa/genética , Humanos , Mutación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genéticaRESUMEN
OBJECTIVE: Cognitive-driven activity of daily living (ADL) impairment in Parkinson's disease (PD) is increasingly discussed as prodromal marker for dementia. Diagnostic properties of assessments for this specific ADL impairment are sparsely investigated in PD. The ability of the Functional Activities Questionnaire (FAQ) for differentiating between PD patients with normal cognition and with mild cognitive impairment (PD-MCI), according to informant and self-reports, was examined. Global cognitive function in groups with and without mild ADL impairment was compared according to different cut-offs. METHODS: Multicenter data of 589 patients of an international cohort (CENTRE-PD) were analyzed. Analyses were run separately for informant-rated and self-rated FAQ. Receiver operating characteristic (ROC) analysis was conducted to define the optimal FAQ cut-off for PD-MCI (≥ 1), and groups were additionally split according to reported FAQ cut-offs for PD-MCI in the literature (≥ 3, ≥ 5). Binary logistic regressions examined the effect of the Montreal Cognitive Assessment (MoCA) score in PD patients with and without mild ADL impairment. RESULTS: Two hundred and twenty-five (38.2%) patients were classified as PD-MCI. For all three cut-off values, sensitivity was moderate to low (< 0.55), but specificity was moderately high (> 0.54) with a tendency of higher values for self-reported deficits. For the self-report, the cut-off ≥ 3 showed a significant effect of the MoCA (B = - 0.31, p = 0.003), where FAQ ≥ 3 patients had worse cognition. No effect for group differences based on informant ratings was detected. CONCLUSION: Our data argue that self-reported ADL impairments assessed by the FAQ show a relation to the severity of cognitive impairment in PD.
Asunto(s)
Disfunción Cognitiva , Enfermedad de Parkinson , Actividades Cotidianas , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Humanos , Pruebas de Estado Mental y Demencia , Pruebas Neuropsicológicas , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Encuestas y CuestionariosRESUMEN
BACKGROUND: A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17. OBJECTIVES: The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations. METHODS: We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled. RESULTS: Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD PEuropean = 6.64 × 10-4 , pooled PD P = 1.15 × 10-11 ). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10-8 ). CONCLUSIONS: Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.