A5053595396- Parkinson's Disease Mechanisms and Treatments
- Cellular transport and secretion
- Immunotherapy and Immune Responses
- Endoplasmic Reticulum Stress and Disease
- Autophagy in Disease and Therapy
- Lysosomal Storage Disorders Research
- Polyamine Metabolism and Applications
- Calcium signaling and nucleotide metabolism
- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- Cancer Immunotherapy and Biomarkers
- Monoclonal and Polyclonal Antibodies Research
- Melanoma and MAPK Pathways
- Phagocytosis and Immune Regulation
- ATP Synthase and ATPases Research
- Animal testing and alternatives
- Nanoparticle-Based Drug Delivery
- Hereditary Neurological Disorders
- Amino Acid Enzymes and Metabolism
- Lipid Membrane Structure and Behavior
- Neurological diseases and metabolism
- Computational Drug Discovery Methods
- Nanoplatforms for cancer theranostics
- Cutaneous Melanoma Detection and Management
- RNA Interference and Gene Delivery
KU Leuven
2013-2024
Transport & Mobility Leuven (Belgium)
2017-2021
Newcastle University
2010-2014
Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration corticospinal motor neurons. In a Bulgarian family with three siblings affected complicated hereditary paraplegia, we performed whole exome sequencing and homozygosity mapping identified homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects this gene have been causally associated Kufor-Rakeb syndrome (#606693), an...
Abstract Superparamagnetic iron oxide nanoparticles (SPIONs) have mainly been used as cellular carriers for genes and therapeutic products, while their use in subcellular organelle isolation remains underexploited. We engineered SPIONs targeting distinct compartments. Dimercaptosuccinic acid-coated are internalized accumulate late endosomes/lysosomes, aminolipid-SPIONs reside at the plasma membrane. These features allowed us to establish standardized magnetic procedures these membrane...
Systemic chemotherapy generally has been considered immunosuppressive, but it become evident that certain chemotherapeutic drugs elicit immunogenic danger signals in dying cancer cells can incite protective antitumor immunity. In this study, we investigated whether locoregionally applied therapies, such as melphalan, used limb perfusion for melanoma (Mel-ILP) produce related effects. human biopsies, Mel-ILP treatment upregulated IL1B, IL8, and IL6 associated with their release patients'...
Recessive loss-of-function mutations in ATP13A2 (PARK9) are associated with a spectrum of neurodegenerative disorders, including Parkinson's disease (PD). We recently revealed that the late endo-lysosomal transporter pumps polyamines like spermine into cytosol, whereas dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted...
Potential loss-of-function variants of ATP13A3, the gene encoding a P5B-type transport ATPase undefined function, were recently identified in patients with pulmonary arterial hypertension (PAH). ATP13A3 is implicated polyamine but its function has not been fully elucidated. In this study, we sought to determine biological vascular endothelial cells (ECs) and how PAH-associated may contribute disease pathogenesis.
Significance ATP13A2 is a lysosomal transporter that genetically linked to an autosomal recessive variant of Parkinson’s disease and confers protection against α-synuclein toxicity in neurons. Here we show N-terminal hydrophobic domain specifically recognizes signaling lipids. Interactions with these lipids enhance cytoprotection mitochondrial stress. This study provides essential information for establishing the function suggests therapeutic applicability activating ATP13A2.
The ingrained capacity of melanoma cells to rapidly evolve toward an aggressive phenotype is manifested by their increased ability develop drug-resistance, evident in the case vemurafenib, a therapeutic-agent targeting BRAFV600E. Previous studies indicated tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports resistance remains unclear. Here, using isogenic human murine...
Polyamines, such as putrescine, spermidine, and spermine, are physiologically important polycations, but the transporters responsible for their uptake in mammalian cells remain poorly characterized. Here, we reveal a new component of polyamine transport system using CHO-MG cells, widely used model to study alternative routes characterize inhibitors therapy. present deficiency resistance toxic biosynthesis inhibitor methylglyoxal bis-(guanylhydrazone) (MGBG), molecular defects these cellular...
Abstract Parkinson’s disease (PD) is a progressive neurodegenerative brain presenting with variety of motor and non-motor symptoms, loss midbrain dopaminergic neurons in the substantia nigra pars compacta occurrence α-synuclein-positive Lewy bodies surviving neurons. Here, we performed whole exome sequencing 52 early-onset PD patients identified 3 carriers compound heterozygous mutations ATP10B P4-type ATPase gene. Genetic screening Belgian dementia (DLB) cohort 4 additional mutation (6/617...
Several human P5-type transport ATPases are implicated in neurological disorders, but little is known about their physiological function and properties. Here, we investigated the relationship between five mammalian P5 isoforms ATP13A1-5 a comparative study. We demonstrated that ATP13A1-4 undergo autophosphorylation, which hallmark P-type ATPase property required for substrate transport. A phylogenetic analysis of sequences revealed ATP13A1 represents clade P5A, highly conserved fungi animals...
ATP13A2 (also called PARK9), is a transmembrane endo-/lysosomal-associated P5 type transport ATPase. Loss-of-function mutations in result the Kufor-Rakeb Syndrome (KRS), form of autosomal Parkinson's disease (PD). In spite growing interest ATP13A2, very little known about its physiological role stressed cells. Recent studies suggest that N-terminal domain may hold key regulatory functions, but their nature remains incompletely understood. To this end, we generated set melanoma and...
Targeting endoplasmic reticulum stress-induced apoptosis may offer an alternative therapeutic strategy for metastatic melanoma. Fenretinide and bortezomib induce of melanoma cells but their efficacy be hindered by the unfolded protein response, which promotes survival ameliorating stress. The aim this study was to test hypothesis that inhibition GRP78, a vital response mediator, increases cell death in combination with stress-inducing agents. Down-regulation GRP78 small-interfering RNA...
The late endo-/lysosomal P-type ATPase ATP13A2 (PARK9) is implicated in Parkinson’s disease (PD) and Kufor-Rakeb syndrome, early-onset atypical Parkinsonism. interacts at the N-terminus with signaling lipids phosphatidic acid (PA) phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2), which modulate activity under cellular stress conditions. Here, we analyzed stable human SHSY5Y cell lines overexpressing wild-type (WT) or mutants three N-terminal lipid binding sites (LBS1–3) were mutated. We...
Abstract The T61I mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a protein residing the mitochondrial intermembrane space (IMS), causes an autosomal dominant form of Parkinson’s disease (PD), but underlying pathogenic mechanisms are not well understood. Here, we compared subcellular localization and solubility wild-type (WT) mutant CHCHD2 human cells. We found that targeting both WT depended on four cysteine residues C-terminal (CHCH) N-terminal predicted...
ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form parkinsonism. Loss-of-function mutations ATP13A2 result lysosomal deficiency as consequence impaired export the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests involvement regulating fate α-synuclein, such cytoplasmic accumulation external release. However, no consensus...
Abstract Polyamines are essential for cell growth and differentiation, but their trafficking by the polyamine transport system is not fully understood. Herein, synthesis of several azido‐derivatized polyamines easy conjugation click chemistry described. Attachment a 4,4‐difluoro‐4‐bora‐3 ,4 ‐diaza‐ s ‐indacene (BODIPY) dye gave fluorescent probes, which were tested in culture. The linear probe series showed superior cellular uptake compared with that probes was attached to branch on one...
ABSTRACT Glucose‐regulated protein 78 (GRP78) is a stress sensor which interacts with unfolded response (UPR) activators in the endoplasmic reticulum (ER). The aim of this study was to test hypothesis that GRP78 has distinct functional roles mediating effects ER neuroblastoma compared other neuroectodermal cancer types. knocked down or overexpressed tumor cell lines. Protein and transcript expression were measured using Western blotting, confocal microscopy, real‐time polymerase chain...