Affiliation

Max Delbrück Center for Molecular Medicine (MDC)

Research Focus

Muscle stem cells face a crucial decision between differentiating to form new muscle or selfrenew to generate anew stem cell. The self-renewal process ensures the maintenance of a cell reservoir for future muscle growth and repair. In our research, we have identified proteins that are produced and degraded in a rhythmic manner within proliferating muscle stem cells, causing oscillations of the proteins. The dynamic presence of these proteins stabilizes a state in which myogenic cells remain undecided whether they will differentiate or self-renew. To delve deeper into this oscillatory network and its regulation, we aim to expand upon our previous analyses in which we used mice as model organisms. Our focus is on studying oscillatory proteins in human myogenic cells derived from induced pluripotent stem cells. Notably, we have observed oscillations in a key regulatory protein, MYOD, in human cells. Utilizing these human cells, our objective is to investigate how these oscillations synchronize between cells and define oscillations in muscle stem cells carrying mutations that cause myopathies in patients.

Affiliation

Max-Planck-Forschungsstelle für die Wissenschaft der Pathogene (MPUSP)

Research Focus

Our lab investigates mechanisms of regulation in processes of infection and immunity with a focus on Gram-positive bacterial human pathogens. Understanding these fundamental mechanisms leads to new findings that can be translated into biotechnological and biomedical applications. A successful example is our recent discovery of an RNA-guided DNA cleavage mechanism harnessed as an RNA programmable genome engineering technology that stems from our analysis of the adaptive immune CRISPR-Cas9 system in bacterial pathogens.

Affiliation

Charité - Universitätsmedizin Berlin

Research Focus

The central nervous system (CNS) depends on the coordinated actions of neurons and glial cells to sustain its remarkable capacity. Our research focuses on how intracellular signalling and cytoskeletal dynamics govern brain homeostasis, synaptic integrity, and resilience during stress or disease. We study these processes at two intimately connected levels: astrocytes and synapses. Astrocytes are essential regulators of neuronal function, maintaining homeostasis, shaping synaptic transmission, and coupling neuronal activity to the vasculature. In response to injury or disease, astrocytes enter a protective state known as reactive astrogliosis, which involves dramatic cytoskeletal and membrane trafficking changes that limit tissue damage and neuroinflammation. We investigate how actin remodeling and intracellular trafficking pathways support astrocyte functions and regulate the blood–brain barrier. In synapses, the actin cytoskeleton also provides structural support, enables receptor trafficking and mediates long-term synaptic changes underlying memory. A current focus is how cytoskeletal regulation is coordinated with stress signaling and autophagy to enhance synaptic resilience. Our work highlights the importance of actin remodeling as a protective mechanism against synapse dysfunction during ageing and in neurodegenerative conditions. By combining live imaging, genetics, CRISPR/Cas9 editing, and molecular analyses, our multidisciplinary program aims to reveal how cytoskeleton-dependent mechanisms in astrocytes and neurons safeguard the CNS. Understanding these protective pathways will not only advance basic neuroscience but also inform therapeutic strategies for brain injury, ageing, and diseases such as Alzheimer’s.

Affiliation

Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)

Research Focus

Synapses are of central importance to information processing in the brain, while, aberrant synapse function underlies major neurological and psychiatric disorders. Synthesis and assembly of presynaptic proteins is essential for the development, maintenance, and plastic modulation of neuronal networks and involves the axonal transport of presynaptic vesicle and active zone proteins synthesized in neuronal somata. We discovered that a rare late endosomal signaling lipid directs the axonal co-transport of synaptic vesicle (SV) and active zone proteins in precursor vesicles (PVs) in human neurons. These PVs were found to be distinct from conventional secretory organelles, endosomes, and degradative lysosomes and are transported by a protein complex comprising the small GTPase Arl8A/B and kinesin KIF1A to the presynaptic compartment. In unpublished studies we found that loss (knockout, KO) of either Arl8A/B or KIF1A in human neurons results in reduced somatic protein translation. Moreover, it has been reported that axonally transported organelles often are associated with mRNAs encoding synaptic and/ or mitochondrial proteins. Based on these data we hypothesize that presynapse assembly, maintenance, and plastic modulation are coordinately controlled by the axonal transport of somatically synthesized proteins in PVs and the local translation of transported mRNAs. To test this hypothesis, we will combine (i) genome editing in human neurons and in mice, (ii) quantitative proteomics using pulsed stable isotope labeling by amino acids in cell culture (pSILAC) together with click-chemistry, (iii) ribosome profiling (Ribo-seq) and puromycin-proximity labeling, (iv) multimodal light and electron microscopy, and (v) functional electrophysiological studies in human neurons and in (vi) in slice preparations from mutant mice. We expect our studies to yield fundamental insights into the contribution of axonal mRNA transport and local translation to presynapse biogenesis, maintenance, plastic modulation and function.

Affiliation

Humboldt-Universität zu Berlin (HU)

Research Focus

During the two previous Neurocure funding periods we have intensely characterized, engineered and modified channelrhodopsins and have provided K-selective, Ca-selective, red-light sensitive and dual functional channelrhodopsin-tandems with a wide application range within Neurocure (AG Jentsch, Larkum, Mikhaylova, Owald, Plested, Schmitz). However, the single channel conductance and the on and off switching kinetics of the gates during the conducting state remained elusive. Recently, in a close collaboration with Klaus Benndorf (Jena), the single channel conductances and the on/off kinetics of the K-selective Channelrhodopsin HcKCR and WiChR (left) could be monitored and characterized. Both show two main conducting stated with variable intermediate states to a different extent depending on the membrane voltage. Within the next Neurocure research program we will further analyze conductances, selectivities, and kinetics of various Cryptophyte Channelrhodopsins in order to understand the fundamental gating and selectivity properties. We will try to adapt the single channel recordings from Xenopus oocytes to neuron-related ND cells by further reducing the noise systematically. We will approach refinement of single-channel recording by testing new screening strategies and materials and develop new programs for data analysis. To understand the substates on a molecular level, we will simulate the open state dynamics at different voltages in collaboration with Han Sun (FMP) and further engineer the ChRs accordingly. The modified ChRs will be functionally tested in neurons, Drosophila and fish in close collaboration with AGs Schmitz, Mikhaylova, Owald and Judkewitz. The overall goal is to improve technology and to provide better tools for optogenetic application in the neurosciences.

Affiliation

Max Delbrück Center for Molecular Medicine (MDC)

Research Focus

Our group investigates why mental health conditions — such as depression, anxiety, and neurodevelopmental disorders — affect people so differently. These conditions are often highly variable, with some individuals experiencing only mild difficulties, while others are profoundly affected in many aspects of daily life. We examine the biology that drives this variability, aiming to uncover mechanisms that make some individuals resilient and others vulnerable. We use mouse models for mental disorders and connect behavioral outcomes with the molecular composition of their neurons and synapses. By linking protein-level changes to specific behavioral patterns, we seek to identify the underlying biological pathways that cause and modify these conditions. In particular, we are interested in sex and gender-based differences, and study how biological sex and hormones shape resilience and risk.

Affiliation

Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP)

Research Focus

Our lab investigates synaptic transmission and plasticity, and how aberrant neurotransmission contributes to brain disorders. Because synapses differ widely in their function, we focus on uncovering the mechanisms that drive functional synaptic diversity. We develop tools that allow us to read the molecular composition of synapses, and combine them with super-resolution microscopy and electrophysiological analysis, with the aim to connect a synapse’s functional state with its molecular profile. We apply these tools to obtain a mechanistic understanding of the molecular changes underlying neurodevelopmental and neurodegenerative disorders, with a particular emphasis on amyotrophic lateral sclerosis (ALS).

Affiliation

Humboldt-Universität zu Berlin (HU)

Research Focus

Axon-carrying-dendrite (AcD) neurons are a distinctive class of excitatory neurons in which the axon originates from a basal dendrite rather than the soma. In these neurons, synaptic inputs onto the axon-carrying dendrite can trigger action potentials without somatic depolarization. This bypasses perisomatic inhibition, granting privileged access to axonal output and enabling participation in specific network oscillations involved in memory consolidation. In the hippocampus, pyramidal neurons with AcD morphology are primarily found in the ventral area, comprising ~50% of neurons there. This clustering suggests that axon origin is spatially programmed to meet circuit-specific demands. Emerging evidence also suggests that structural and functional differences between AcD and non-AcD neurons, such as AIS plasticity, may be modulated by neuronal activity, raising the possibility that AcD neuron proportions could undergo experience-dependent reorganization (Lehmann et al., 2023, Han et al., 2024). This plasticity may decline with aging and is disrupted in neurodegenerative diseases like Alzheimer’s (AD), where dendritic architecture, AIS integrity, and synaptic function deteriorate (Criscuolo et al., 2023). Whether these changes affect AcD neuron function remains unknown. Our primary aim is to identify key factors promoting local AcD neuron formation in the ventral hippocampus (vHC) and to uncover the underlying molecular mechanisms. We will first assess whether AcD neuron clustering in the vHC correlates with specific network activities (e.g., sharp wave ripples), as preliminary data suggest neuronal activity facilitates AcD formation (Lehman et al., BioRxiv). We will also investigate which cellular and molecular components drive AcD neuron formation and transformation in adulthood—focusing on microtubule dynamics and MAPs such as Tau and TRIM46, which are critical for axon formation and AIS development. The vHC is closely linked to episodic memory, and since episodic memory impairment is a hallmark of AD, we will quantify AcD neuron populations in the vHC of AD patients. These results will help determine whether AcD neurons are more vulnerable to aging-related cognitive decline.

Affiliation

Max Delbrück Center for Molecular Medicine (MDC) Berlin Institute for Medical Systems Biology (BIMSB)

Research Focus

Our main goal is to unravel the diverse mechanisms of mammalian gene regulation and their roles in development and disease. We have developed Genome Architecture Mapping (GAM), an orthogonal 3D genome folding mapping technology which yields fine maps of chromatin contacts from small cell numbers (500-1000), and is uniquely powerful to quantify different metrics of 3D genome structure, such as multiway contacts and chromatin melting. With immuno-GAM, we introduced the selection of cell types from complex tissues to enable the application of GAM in rare cells, such as hippocampal pyramidal glutamatergic neurons. GAM is an inherently suited platform for multimodal molecular phenotyping of biological samples, from genome sequence and 3D structure, to transcript and protein quantification. More specifically, within our cluster we will work on the following topics: 1.Perturbations to Chromatin in developmental disorders (e.g. mutations in HP1γ, ATRX, CTCF, SATB2, Shank3) and the effects of epileptic agents. With the help of transgenic mice, we will analyse changes to epigenomic integrity, gene expression and physiology. In close collaboration with Andrew Newman (Charite), Nathalie Berube (London, Canada), Lucia Peixoto (Washington State University), Angel Barco (Alicante), and Georg Dechant (Innsbruck, Austria). 2. Chromatin in Neurodegeneration. In close collaboration with Susanne Wegmann from the DZNE, we will investigate chromatin architectures preceding and following neurodegeneration, such as under pathogenic Tau.

Affiliation

Max Delbrück Center for Molecular Medicine (MDC) Berlin Institute for Medical Systems Biology (BIMSB)

Research Focus

How RNA’s are organized to carry out functions in the spatial and temporal organization of polarized cells such as neurons is still a fundamentally unresolved question in Biology, including systems where RNA localization has been linked to disease mechanisms (e. g. Engel et al. 2020, Agrawal and Welshhans 2021). Important questions are how RNA is trafficked into specific compartments, how their function (including translation) is regulated in these compartments, and how the phenotypes are associated with perturbations. We have started a multi-faceted approach to get some new insights into these questions: 1) To systematically quantify the presence of RNA in neuronal compartments at 0.6 micron resolution, and for 100K cells in one experiment, we are adapting our recently published OPEN-ST (spatial transcriptomics in 3D, at subcellular resolution) (Schott et al Cell 2024) including preparing the flow-cell surface with coatings to promote neuronal adhesion and polarity, optimizing conditions for cultured cells to maximize RNA capture efficiency, and applying the established library preparation and analysis stack of Open-ST with computational adjustments for neurite-rich morphologies. With this setup, transcripts can be mapped across subcellular compartments, including soma, proximal and distal dendrites, and axons, using compartment markers registered to the capture array. This design may allow near-organelle quantification of RNAs and, importantly, enables activity-dependent profiling by applying stimuli such as KCl, bicuculline, BDNF, or forskolin directly on the flow-cell. Fixation at defined intervals then captures transcriptional waves, preserving the spatial and temporal context of dynamic RNA regulation. Since thousands of neuronal mRNAs exhibit compartment-specific localization, this approach can directly address key knowledge gaps in how local translation and trafficking logic support synaptic plasticity and neuronal maintenance. 2) In addition to transcript localization, RNA modifications provide another layer of regulation. Marks such as m6A, which modulates RNA stability and translation, and pseudouridine, which strengthens RNA structure, fine-tune neuronal gene expression. To capture these events within our spatial framework, we will implement enzymatic or chemical modifications directly into the Open-ST workflow. This allows modified transcripts to be preserved and later detected in sequencing output, thereby linking subcellular RNA localization with its chemical state. Combining spatial transcriptomics with modification-aware analysis reveals not only where RNAs reside, but also how their chemical regulation supports neuronal plasticity and, when disrupted, contributes to disease. 3) We are developing machine learning methods (GNN’s) and learning on ST data of various formats (incl. MerFish) to learn subcellular localization patterns of RNA molecules to predict RNA localization and derive from these insights into their functions.

Affiliation

Charité – Universitätsmedizin Berlin

Research Focus

Advances in genomic analysis provide new opportunities to uncover the genetic origins of neurological disorders. Induced pluripotent stem cell (iPSC)–derived human neurons represent a powerful platform to directly investigate neural network dysfunctions, including excitation–inhibition imbalance. We will establish an experimental workflow to generate an in vitro culture system composed of the three major cell types of neuronal networks: glutamatergic neurons, GABAergic neurons, and astrocytes, all derived from iPSC lines. The cellular biology and anatomical organization of these networks will be characterized using advanced microscopy. Gene expression patterns will be analyzed at single-cell resolution using transcriptomic techniques. To study synaptic transmission and excitation–inhibition balance, we will combine electrophysiological recordings with optical methods capable of detecting glutamate and GABA release. To model disease pathophysiology, we will employ CRISPR-Cas–mediated genome editing in iPSC lines, enabling us to mimic mutation-driven alterations in neuronal function. This strategy will provide insight into how genetic variants contribute to dysfunctional neural networks underlying neurological disorders. Finally, we will apply this platform to evaluate pharmacological and genetic interventions aimed at restoring balanced network activity. This work will enhance translational pipelines from bench to bedside, ultimately improving our ability to investigate and treat the pathophysiology of neurological diseases.

Affiliation

Max Delbrück Center for Molecular Medicine (MDC) Berlin

Research Focus

The Sanders Lab studies how somatic mutations arise and shape cell states in health and disease. By developing and applying single-cell and multi-omic methods, the lab investigates genome instability processes and their impact on cellular phenotypes. The goal is to understand how genetic mosaicism emerges, evolves, and contributes to tissue function and disease

Affiliation

Freie Universität Berlin

Research Focus

Feeding and metabolism are central to survival and have a profound impact on general health, influencing processes ranging from growth and energy balance to susceptibility to metabolic and psychiatric disorders. Understanding how feeding decisions are regulated at the cellular and circuit level therefore represents a key biological question. In addition, altered metabolic states can compromise cognitive functioning, emphasizing the tight integration of metabolic health with higher-order brain function. The fruit fly Drosophila melanogaster offers an ideal system to uncover fundamental principles, owing to its genetic accessibility, conserved neuromodulatory pathways, and powerful behavioral and physiological assays. Serotonin (5-HT) is a highly conserved regulator of hunger and satiety, yet the cellular and metabolic mechanisms through which it acts remain poorly defined. Emerging evidence suggests that 5-HT influences both mitochondrial function in neurons and metabolic activity in glial cells, processes essential for maintaining excitability and energy balance. Moreover, selective 5-HT reuptake inhibitors (SSRIs) are widely used in psychiatry but their impact on neuronal metabolism and feeding behavior is not well understood. This project aims to dissect how serotonin shapes feeding behavior in Drosophila through three complementary approaches. First, the interaction between 5-HT and co-expressed neuropeptides will be analyzed to clarify how hunger and satiety states are encoded. Second, mitochondrial adaptations in serotonergic neurons under starvation will be investigated to link metabolic plasticity with neurotransmission. Third, 5HT–glia coupling will be studied with a focus on how 5HT and SSRIs influence glial metabolism and feeding behavior. Finally, we will assess how these modulations interact with memory systems to guide cognitive processes, particularly selective memory consolidation. By integrating behavioral assays with advanced biosensors and genetic manipulations, this work will reveal how 5-HT coordinates cellular energy states and circuit dynamics to control feeding and higher cognitive tasks. The findings will not only establish a mechanistic framework for 5HT’s role in nutrient sensing but also provide insight into how pharmacological interventions such as SSRIs alter metabolism and behavior.

Affiliation

Charité – Universitätsmedizin Berlin

Research Focus

Our lab is interested in synapses and neuronal circuits, both in health and disease. In order to achieve our goals we use a multidisciplinary approach. By combining single to multicell recordings, we try to understand the role of individual neuron types in complex networks. Furthermore, we use optobiology (e.g. functional microscopy, optogenetics) to understand the dynamics of neuronal processes. More specifically, within our cluster we will work on the following topics: 1. Neuronal circuits. How do neuronal networks generate oscillatory activity and how is this activity propagating within and into different brain areas. In addition, we will study the connectivity between different brain regions and the role of these interactions in behaviour. This work will be done in collaboration with Michael Brecht 2. Pathophysiology of developmental disorders such as autism (e.g. mutations in SHANK) and epilepsy (e.g. SYNGAP). With the help of transgenic animals (both mice and rats) we will analyse the pathology of the disease. In close collaboration with Markus Schülke from the clinical department and Ralf Kühn (MDC) and Sarah Shoichet (Charité) we are also planning to develop a proof-of-principle concept for gene therapy. 3. Auto-immune encephalitis. In fruitful collaboration with Harald Prüss and Susanne Wegmann from the Department of Neurology and the DZNE we are investigating the role of antibodies (e.g. NMDA, LGI-1 etc) in neurological & psychiatric disorders. Furthermore, we will develop new therapeutic interventions using cell therapy (CAART).

Affiliation

Humboldt Universität zu Berlin, Institute for Theoretical Biology

Research Focus

Neuronal networks display a remarkable richness of collective behaviors – from tightly synchronized rhythms to chaotic activity – that are often altered in neurological disease. These states emerge from the interplay between network connectivity and countless cellular mechanisms, yet our mechanistic understanding of which cellular features drive or constrain such dynamics remains incomplete. Our recent studies highlight how the fine-scale dynamics of individual neurons can propagate to the macroscopic level, fostering synchronization, desynchronization, or chaotic transitions. In this project, we aim to unravel the less obvious determinants of such dynamics. Rather than attributing excitability and neural dynamics solely to action-potential generating ion channels, we explore a wider landscape: dendritic and axonal arborization, the activity of ion pumps such as Na⁺/K⁺-ATPase, neuromodulatory and peptidergic influences, dendritic ion channel properties, receptor kinetics, and the energetic status of mitochondria. By focusing on the spatial organization of these parameters across neuronal compartments, we seek to uncover how subtle intrinsic differences reconfigure excitability, producing network-level consequences such as aberrant rhythmicity or depolarization block – phenomena closely linked to disease states. Leveraging advanced mathematical modeling informed by increasingly detailed experimental datasets of high spatial resolution, this project seeks to provide a mechanistic framework connecting single-cell biophysics to pathological network activity, with the long-term goal of identifying novel intervention points in brain disorders.

Affiliation

Freie Universität Berlin (FU)

Research Focus

Our future research will explore how intracellular organelle dynamics and local synaptic mechanisms jointly safeguard brain function during aging. Using Drosophila as a genetically tractable model, we aim to dissect how synaptic resilience is maintained or lost in the face of advancing age, with particular emphasis on presynaptic remodeling, autophagic flux, and mitochondrial function. Building on our prior work on synaptic scaffold dynamics and presynaptic plasticity, we now focus on how aging affects the trafficking and integration of organelles such as endosomes, lysosomes, and mitochondria at synaptic sites. We are particularly interested in identifying conserved molecular modules that mediate the coupling between metabolic state, organelle positioning, and synaptic integrity. Combining high-resolution imaging, functional readouts, and proteomic profiling in aging Drosophila brains, we aim to reveal how age-dependent changes in organelle function contribute to synaptic decline. In parallel, we will develop tools to selectively manipulate these modules in space and time, both to understand their fundamental roles and to test potential interventions. Through comparative studies with mammalian systems, including collaborations within the NeuroCure network, our work aspires to identify shared principles of brain maintenance and resilience. In the long term, we hope to contribute to translational strategies aimed at preserving cognitive function in aging and neurodegenerative disease.

Affiliation

Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)

Research Focus

Intraneuronal accumulation of phosphorylated Tau is a pathological hallmark in < 20 neurological conditions and correlates with synapto- and neurotoxic in Tau-related neurodegenerative diseases. This includes Alzheimer’s disease and frontotemporal dementia subtypes but also conditions like stroke, epilepsy, and autoimmune disorders, which have a pronounced dysregulation of neuronal activity (acute, long-term, or reoccurring hyperexcitation) in common. Finding the specific and common mechanisms that underlie the pathophysiological Tau “activation” in this diverse set of brain disorders would be an important step towards the design of disease-tailored and general Tau-targeted intervention therapies. We propose that aberrant and exuberated neuronal/network activity patterns are upstream of physiological Tau activation in the brain - as part of a activity stress response mechanism-, which can transition into pathological Tau toxicity and aggregation upon their prolonged or reoccurring occurrence. To test this idea, we will disentangle the relation between neuronal activity and Tau “activation”, in general and in disease relevant conditions. We propose to: (1) Quantify the amount, duration and pattern of neuronal excitation needed to induce Tau missorting by using different optogenetic tools (Ca2+ sensors, channelrodopsins) in combination with Tau molecular imaging (nanobodies, endogenous tagging, light- or DOX-induced Tau expression) in mouse neuronal cultures and organotypic wt mouse brain slices. (2) Quantify and compare neuronal activity patterns induced by disease-relevant conditions triggering Tau; this includes application of Abeta peptides, seizure triggering substances, autoimmune antibodies, and glucocorticoids, in combination with Calcium imaging in vitro, in slice cultures, and in vivo. These data will be backed up with histological assessment of Tau changes in existing animal models of the Abeta, stroke, and epilepsy and chronic stress. (3) Test whether neuronal activity modulation (chemical, DREADDS) can prevent Tau phosphorylation, missorting and pathology in mouse and human neurons/organoids, and in animal models of autoimmune encephalitis (e.g., IgLON5) using histological and biochemical assessments. This work program bridges betwee the Aging and Maintenance parts of NeuroCure.