A5083637599- Parkinson's Disease Mechanisms and Treatments
- Pluripotent Stem Cells Research
- Mitochondrial Function and Pathology
- Nuclear Receptors and Signaling
- Neurological disorders and treatments
- Cell Image Analysis Techniques
- CRISPR and Genetic Engineering
- Autophagy in Disease and Therapy
- Science, Research, and Medicine
- Health and Medical Research Impacts
- Pharmaceutical industry and healthcare
- Genetic Neurodegenerative Diseases
- Gene Regulatory Network Analysis
- Neurogenesis and neuroplasticity mechanisms
- Neuroinflammation and Neurodegeneration Mechanisms
- 3D Printing in Biomedical Research
- Neuroscience and Neuropharmacology Research
- Metabolism, Diabetes, and Cancer
- Single-cell and spatial transcriptomics
- Nerve injury and regeneration
- Immune cells in cancer
- Neuroscience and Neural Engineering
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Endoplasmic Reticulum Stress and Disease
University of Luxembourg
2015-2025
Amrita Institute of Medical Sciences and Research Centre
2024
Luxembourg Institute of Health
2020-2022
Centre Hospitalier de Luxembourg
2016
University of Maryland, Baltimore
2015
Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact aetiology remains largely unknown. To date, research has mainly focused on nigral although recent studies suggest disease-related changes also in non-neuronal cells and midbrain regions beyond substantia nigra. While there some evidence for glial involvement disease, molecular mechanisms remain poorly understood. The aim this study was to characterize contribution all cell types...
Modeling Parkinson's disease (PD) using advanced experimental in vitro models is a powerful tool to study mechanisms and elucidate unexplored aspects of this neurodegenerative disorder. Here, we demonstrate that three-dimensional (3D) differentiation expandable midbrain floor plate neural progenitor cells (mfNPCs) leads organoids resemble key features the human midbrain. These are composed dopaminergic neurons (mDANs), which produce secrete dopamine. Midbrain-specific derived from PD...
The immortalized and proliferative cell line SH-SY5Y is one of the most commonly used lines in neuroscience neuroblastoma research. However, undifferentiated cells share few properties with mature neurons. In this study, we present an optimized neuronal differentiation protocol for that requires only two work steps 6 days. After differentiation, increased levels ATP plasma membrane activity but reduced expression energetic stress response genes. Differentiation results mitochondrial...
The human neuroblastoma cell line, SH-SY5Y, is a commonly used line in studies related to neurotoxicity, oxidative stress, and neurodegenerative diseases. Although this often as cellular model for Parkinson's disease, the relevance of context disease (PD) other diseases has not yet been systematically evaluated. We have systems genomics approach characterize SH-SY5Y using whole-genome sequencing determine genetic content transcriptomics proteomics data molecular correlations. Further, we...
Human midbrain-specific organoids (hMOs) serve as an experimental in vitro model for studying the pathogenesis of Parkinson's disease (PD). In hMOs, neuroepithelial stem cells (NESCs) give rise to functional midbrain dopaminergic (mDA) neurons that are selectively degenerating during PD. A limitation hMO is under-supply oxygen and nutrients densely packed core region, which leads eventually a "dead core". To reduce this phenomenon, we applied millifluidic culture system ensures media supply...
Abstract Parkinson's disease (PD)‐specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient‐specific derived from induced pluripotent stem cells carrying the LRRK2‐G2019S mutation, is optimized 3D microfluidics. automated image analysis algorithms are implemented to enable pharmacophenomics disease‐relevant conditions. In contrast this approach reveals robust High‐content imaging data show decreased dopaminergic differentiation...
Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), regulates clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay nuclear- and mitochondrial-encoded proteins, recent studies suggest that influences this process at both levels. In addition, was shown to prevent mitochondrial membrane permeability, impeding DNA (mtDNA) escape subsequent neuroinflammation. However,...
Parkinson's disease (PD) is a complex, progressive neurodegenerative characterized by the loss of dopaminergic neurons in substantia nigra pars compacta midbrain. Despite extensive research efforts, molecular and cellular changes that precede neurodegeneration PD are poorly understood. To address this, here we describe use patient specific human midbrain organoids harboring SNCA triplication to investigate mechanisms underlying degeneration. Our organoid model recapitulates key pathological...
Growing evidence indicates that type 2 diabetes (T2D) is associated with an increased risk of developing Parkinson's disease (PD) through shared mechanisms. Studies show insulin resistance, which the driving pathophysiological mechanism T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism and survival. To investigate resistance caused pathological changes human midbrain, could predispose healthy midbrain to PD development, we exposed iPSC-derived...
Immunoresponsive gene 1 (IRG1) is one of the highest induced genes in macrophages under pro-inflammatory conditions. Its function has been recently described: it codes for immune-responsive protein/cis-aconitic acid decarboxylase (IRG1/CAD), an enzyme catalysing production itaconic from cis-aconitic acid, a tricarboxylic (TCA) cycle intermediate. Itaconic possesses specific antimicrobial properties inhibiting isocitrate lyase, first glyoxylate shunt, anaplerotic pathway that bypasses TCA and...
Aims: The outer mitochondrial membrane protein Miro1 is a crucial player in dynamics and calcium homeostasis. Recent evidence indicated that mediates calcium-induced shape transition, which prerequisite for the initiation of mitophagy. Moreover, altered levels have emerged as shared feature monogenic sporadic Parkinson's disease (PD), but, so far, no disease-associated variants RHOT1 been identified. Here, we aim to explore genetic functional contribution mutations PD patient-derived...
Brain organoids are highly complex multi-cellular tissue proxies, which have recently risen as novel tools to study neurodegenerative diseases such Parkinson's disease (PD). However, with increasing complexity of the system, usage quantitative becomes challenging.The primary objective this was develop a neurotoxin-induced PD organoid model and assess neurotoxic effect on dopaminergic neurons using microscopy-based phenotyping in high-content fashion.We describe pipeline for machine...
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 disease. Biallelic in phosphatase tensin homolog (PTEN)-induced putative kinase 1 (PINK1) involved mitochondrial homeostasis, vesicle trafficking, autophagy sufficient cause PD.We sought evaluate difference between controls' PINK1 patients' derived neurons their transition from neuroepithelial stem cells neurons,...
Abstract Background Specific microglia responses are thought to contribute the development and progression of neurodegenerative diseases, including Parkinson’s disease (PD). However, phenotypic acquisition microglial cells their role during underlying neuroinflammatory processes remain largely elusive. Here, according multiple-hit hypothesis, which stipulates that PD etiology is determined by a combination genetics various environmental risk factors, we investigate transcriptional programs...
The gut is proposed as a starting point of idiopathic IPD, but the presence α-synuclein in IPD colon mucosa debated.The objective this study was to evaluate if can serve biomarker IPD.Immunohistochemistry used locate and quantify blinded approach from biopsies right left 19 patients 8 controls.Total present all 1 controls; phosphorylated subjects. There no intensity difference depending on disease status. Staining total stronger (p = .04).Conventional immunohistochemistry staining mucosal...
Abstract Mitochondrial Rho GTPase 1 (Miro1) protein is a well-known adaptor for mitochondrial transport and also regulates quality control function. Furthermore, Miro1 was associated with mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs), which are key regulators of cellular calcium homeostasis the initiation autophagy. Impairments these mechanisms were linked to neurodegeneration in Parkinson’s disease (PD). We recently revealed that PD fibroblasts harboring mutations displayed...
VPS35 is part of the retromer complex and responsible for trafficking recycling proteins implicated in autophagy lysosomal degradation, but also takes degradation mitochondrial via mitochondria-derived vesicles. The p.D620N mutation causes an autosomal-dominant form Parkinson's disease (PD), clinically representing typical PD.Most studies on were performed human tumor cell lines, rodent models overexpressing mutant VPS35, or patient-derived fibroblasts. Here, based identified target...
Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many the PD-associated proteins involved mitochondrial quality control, e.g., PINK1, Parkin, LRRK2, which were recently identified as regulators mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs) linking homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly...
In briefWalter et al. show that differentiating iPSC-derived neurons carrying the LRRK2-G2019 mutation are characterized by faster initial neuronal differentiation and cell-cycle exit, as well increased cell death, compared to controls.Downregulation of transcription factor NR2F1 appears key mediate LRRK2-G2019S-dependent phenotypes.
Parkinson’s disease (PD) is a neurodegenerative with unknown cause in the majority of patients, who are therefore considered “idiopathic” (IPD). PD predominantly affects dopaminergic neurons substantia nigra pars compacta (SNpc), yet pathology not limited to this cell type. Advancing age main risk factor for development IPD and greatly influences function microglia, immune cells brain. With increasing age, microglia become dysfunctional release pro-inflammatory factors into extracellular...