A5033711333- Calcium signaling and nucleotide metabolism
- Retinal Development and Disorders
- Neuroscience and Neuropharmacology Research
- Photoreceptor and optogenetics research
- Cellular transport and secretion
- Ion Channels and Receptors
- Lysosomal Storage Disorders Research
- Advanced Fluorescence Microscopy Techniques
- Adenosine and Purinergic Signaling
- Neonatal Health and Biochemistry
- Autoimmune Bullous Skin Diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- T-cell and B-cell Immunology
- Tryptophan and brain disorders
- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Immune Cell Function and Interaction
- Hereditary Neurological Disorders
- Cell Image Analysis Techniques
- Platelet Disorders and Treatments
- Plant Molecular Biology Research
- Urticaria and Related Conditions
- Monoclonal and Polyclonal Antibodies Research
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Advanced Biosensing Techniques and Applications
Massachusetts General Hospital
2019-2024
LMU Klinikum
2015-2024
Ludwig-Maximilians-Universität München
2014-2024
Max Planck Institute for Brain Research
2014-2024
Max Planck Institute of Psychiatry
2011-2020
Harvard University
2019-2020
Center for Integrated Protein Science Munich
2014-2018
German Centre for Cardiovascular Research
2016
Max Planck Society
2013
University of Lübeck
2010
Cytokines and chemokines are produced secreted by a broad range of immune cells including macrophages. Remarkably, little is known about how these inflammatory mediators released from the various cells. Here, endolysosomal cation channel TRPML2 shown to play direct role in chemokine trafficking secretion murine To demonstrate acute involvement processes, first isoform-selective agonist was generated, ML2-SA1. ML2-SA1 not only found directly stimulate release CCL2 macrophages but also...
Lung emphysema and chronic bronchitis are the two most common causes of obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, known to mediate development lung injury emphysema. Here, we discovered endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator MMP-12 reuptake broncho-alveolar fluid, driving in independently generated Trpml3-/- mouse models enlarged injury, further exacerbated after or tobacco smoke...
Significance Polymorphisms in the endolysosomal cation channel TPC2 have been suggested to lead a shift human hair color from brown blond. In two further studies role for melanosomal pH regulation was postulated. Electrophysiological data on how these polymorphisms affect gating and activity are, however, missing. We show here that both gain of function by different mechanisms. M484L sensitivity its endogenous ligand PI(3,5)P 2 is strongly increased while G734E inactivation ATP reduced....
Abstract Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of autoantibody formation and thus treatments directly stabilizing keratinocyte adhesion would fulfill an unmet medical need. We here demonstrate that apremilast, phosphodiesterase 4 inhibitor used in psoriasis, prevents pemphigus vulgaris. Apremilast abrogates autoantibody-induced loss cohesion ex-vivo human epidermis,...
In the vertebrate retina, several dozens of parallel channels relay information about visual world to brain. These are represented by different types retinal ganglion cells (RGCs), whose responses rendered selective for distinct sets features various mechanisms. mechanisms can be roughly grouped into synaptic interactions and cell-intrinsic mechanisms, with latter including dendritic morphology as well ion channel complement distribution. Here, we investigate how strongly shape RGC output...
Endolysosomes are dynamic, intracellular compartments, regulating their surface-to-volume ratios to counteract membrane swelling or shrinkage caused by osmotic challenges upon tubulation and vesiculation events. While osmosensitivity has been extensively described on the plasma membrane, mechanisms underlying endolysosomal ratio changes identities of involved ion channels remain elusive. mediate endocytosis, exocytosis, cargo transport, sorting material for recycling degradation. We...
We show that the combination of an intracellular bi-partite calmodulin (CaM)-binding site and a distant assembly region affect how ion channel is regulated by membrane lipid. Our data reveal regulation phosphatidylinositol(4,5)bisphosphate (PIP2) stabilization assembled Kv7.2 subunits coiled-coil regions far from are coupled molecular processes. Live-cell fluorescence energy transfer measurements direct binding studies indicate remote formation creates conditions for different CaM...
Fluorescence resonance energy transfer (FRET) is a powerful method for the detection and quantification of stationary dynamic protein-protein interactions. Technical limitations have hampered systematic in vivo FRET experiments to study interactions their native environment. Here, we describe rapid robust protocol that combines adeno-associated virus (AAV) vector-mediated delivery genetically encoded partners with ex measurements. The was established on acutely isolated outer segments murine...
Outer segments (OSs) of rod photoreceptors are cellular compartments specialized in the conversion light into electrical signals. This process relies on light-triggered change intracellular levels cyclic guanosine monophosphate, which turn controls activity nucleotide-gated (CNG) channels OS plasma membrane. The CNG channel is a macromolecular complex that its core harbors ion-conducting CNGA1 and CNGB1a subunits. To identify additional proteins interact with subunit, we applied affinity...
We studied the retinal rod pathway of Carollia perspicillata and Glossophaga soricina , frugivorous microbats phyllostomid family. Protein kinase Cα (PKCα) immunolabeling revealed abundant bipolar cells (RBCs) with axon terminals in innermost sublamina inner plexiform layer (IPL), which is typical for mammals. Extraordinarily, RBC axons showed additional synaptic contacts a second further out IPL. Dye injections PKCα-prelabeled RBCs C. confirmed bistratified morphology. The functional...
Alterations in the autophagosomal–lysosomal pathway are a major pathophysiological feature of CLN3 disease, which is most common form childhood-onset neurodegeneration. Accumulating autofluorescent lysosomal storage material consisting dolichols, lipids, biometals, and protein that normally resides mitochondria, subunit c mitochondrial ATPase, provides evidence turnover cellular components disrupted upon loss function. Using murine neuronal cell model accurately mimics gene defect hallmark...
We studied the retinal cone bipolar cells of Carollia perspicillata, a microchiropteran bat phyllostomid family. Microchiroptera are strongly nocturnal, with small eyes and rod-dominated retinae. However, they also possess significant population (2-4%) comprising two spectral types, which hence basis for daylight color vision. used antibodies against calcium-binding protein recoverin carbohydrate epitope 15 (CD15) as reliable markers certain cells. Dye injections recoverin- or...
Abstract Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) have a complex aetiology with alterations of both the intestinal epithelial barrier and IL23/IL17 immune response. Here, we investigated role novel mutation in desmosomal cadherin desmoglein 2 gene ( DSG2 ) pathogenesis IBD. is known to regulate integrity. Genetic analysis CD patient revealed likely pathogenic leading truncated protein lacking part intracellular domain. We generated an enterocyte-specific mouse model,...
Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3∆ex7/8 mice, a genetically accurate disease model. Loss lysosomal storage material accumulation abnormal morphology subcellular organelles. Moreover, pathological proteomic signatures are indicative defects lipid metabolism....
Mutations in the photoreceptor outer segment (OS) specific peripherin-2 lead to autosomal dominant retinitis pigmentosa (adRP). By contrast, mutations homolog Rom-1 cause digenic RP combination with certain heterozygous peripherin-2. The mechanisms underlying differential role of and pathophysiology remained elusive so far. Here, focusing on two adRP-linked mutants, P210L C214S, we analyzed binding characteristics, protein assembly, rod OS targeting wild type (perWT), mutant (perMT), or...
Peripherin-2 is a glycomembrane protein exclusively expressed in the light-sensing compartments of rod and cone photoreceptors designated as outer segments (OS). Mutations peripherin-2 are associated with degenerative retinal diseases either affecting or photoreceptors. While has been extensively studied rods, there only little information on its supramolecular organization function cones. Recently, we have demonstrated that interacts light detector rhodopsin OS rods. It remains unclear,...
Background: Microglia are the primary brain cell type regulating neuroinflammation and they important for healthy aging. Genes microglial function associated with an increased risk of neurodegenerative disease. Loss-of-function mutations in CLN3, which encodes endolysosomal membrane protein, lead to most common childhood-onset form neurodegeneration, featuring early-stage that long precedes neuronal loss. How loss CLN3 leads this early is not yet understood. Methods: Here, we have...