Biology subjects

Schwarz, Y.

Publications and source records attributed to Schwarz, Y..

4 recordsLinked to original sources

bioRxiv2025

Distinct Flower signaling domains orchestrate cellular fitness via secreted vesicles in Aβ-induced neurodegeneration

Cellular fitness surveillance preserves tissue integrity, yet its regulation within the mammalian brain remains poorly understood. We identify a bifurcated mechanism in the transmembrane protein Flower--encoding both survival-promoting ("win") and apoptosis-inducing ("lose") isoforms. We demonstrate that astrocytes secrete specialized extracellular vesicles (EVs), termed "fitness vesicles," carrying Flower to facilitate competitive selection across distal cell populations. The N-terminal Flower domain acts extrinsically via these EVs to drive the elimination of less-fit neighbors. Conversely, the "win"-specific C-terminal domain functions as a cell-intrinsic module; it translocates to the nucleus under stress to repress Caspase-3 and provide resilience. In Alzheimers disease (AD) models and human AD brains, Flower-positive astrocytes accumulate around amyloid-{beta} (A{beta}) plaques. Under A{beta} stress, the "win" isoform reprograms astrocytes toward a neuroprotective state that enhances plaque clearance while ensuring cell-intrinsic survival. Our findings reveal how Flower couples long-range, EV-mediated cellular selection with cell-autonomous protection to coordinate astrocyte quality control and tissue resilience in neurodegeneration.

neuroscience↗

bioRxiv2024

Ideal efficacy photoswitches for TRPC4/5 channels harness high potency for spatiotemporally-resolved control of TRPC function in live tissues

Directly probing the endogenous biological roles of target proteins with high spatial and temporal resolution, as non-invasively and reproducibly as possible, is a shared conceptual goal for research across many fields, as well as for targeted therapies. Here we describe the rational conceptual design and test-case practical implementation of a photopharmacological paradigm to empower high-performance photomodulation studies in vivo. TRPC4/5 ion channels are involved in many spatiotemporally resolved circuits, from pain and anxiety, to reproductive signaling, digestion, and obesity. To unpick their biology requires spatiotemporally precise tools, which were lacking. We developed "ideal efficacy photoswitch" ligands to control their diverse functions in situ. These E{leftrightarrows}Z-photoswitchable ligands bias TRPC[4]/5 channel activity with exquisite photocontrol, from strong agonism under 360 nm, to low agonism at 385 nm, to strong antagonism at 410-460 nm. Cryo-EM structures of both TRPC4 and TRPC5 with both Z-agonists and E-antagonists support the rationale for efficacy switching through competitive E/Z isomer binding. Crucially, since the E/Z ratio is exclusively determined by the light wavelength applied, their channel photocontrol is exclusively wavelength-dependent, yet drug-concentration-independent: so is reproducible from cell culture to >millimetre-depth tissues. Indeed, we were able to photocontrol both direct and downstream TRPC4/5 biology in cell lines or primary cells in culture, from calcium flux, to primary neuron excitability and adrenaline release; and even in tissues, photoswitching small intestine motility and peristalsis. The TRPC4/5 ligands we develop will thus unlock a range of high-precision investigations in TRP biology. More broadly, we propose that the success of this efficacy photoswitch program, from concept to tissue level translation, is mainly a consequence of how biology has evolved proteins for efficacy control. We therefore foresee that a variety of functionally responsive protein targets, not only sensory and signaling ion channels and receptors, will be amenable to similarly high-performance photocontrol even in vivo, if a new generation of reagent development adopts this paradigm of ideal efficacy photoswitching. Table of Contents Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/602451v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1f8e527org.highwire.dtl.DTLVardef@18c72d0org.highwire.dtl.DTLVardef@1c5d648org.highwire.dtl.DTLVardef@177203d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Multicore-fiber microendoscopy for functional cellular in-organ imaging

Microendoscopy enables minimally invasive investigations of organs even within small cavities. Conventional microendoscopy is limited by probe size and often restricted to a single excitation wavelength. We developed and characterized a multichannel microendoscope as thin as 360 {micro}m and recorded functional cellular signals in-situ using custom written software for image processing. The endoscope had an effective resolution of 4.64 {micro}m and resolved subcellular structures of neurons. The system enabled analysis of in-situ calcium responses in murine tracheal brush cells and kidney podocytes. Additionally, ratiometric redox responses were recorded in whole, explanted organs and pancreatic islet culture. The flexibility and simplicity of our approach for imaging a variety of tissues and organs paves the way for in-vivo, longitudinal studies with cellular resolution.

bioengineering↗

bioRxiv2020

Alternative splicing switches STIM1 targeting to specialized membrane contact sites and modifies SOCE

Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator molecule of store-operated Ca2+ entry (SOCE) and a sorting regulator of certain ER proteins such as Stimulator of interferon genes (STING). Here, we characterize a conserved new variant, Stim1A, where splice-insertion translates into an additional C-terminal domain. We find prominent expression of exonA mRNA in testes, astrocytes, kidney and heart and confirm Stim1A protein in Western blot of testes. In situ, endogenous Stim1 with domain A, but not Stim1 without domain A localizes to unique adhesion junctions and to specialized membrane retrieval sites (tubulobulbar complexes) in testes. Functionally, using Ca2+ imaging and patch-clamp analysis, Stim1A shows a dominant-negative effect on SOCE and ICRAC, despite normal clustering and interaction with Orai1 investigated by combined TIRF and FRET analyses and as confirmed by an increased SOCE upon knock-down of endogenous Stim1A in astrocytes. Mutational analyses in conjunction with imaging and patch-clamp analyses of residues either in domain A or within the N-terminal region of Orai1 demonstrate a specific defect in stabilized channel gating. Our findings demonstrate that cell-type specific splicing of STIM1 adds both an intracellular targeting switch and adapts SOCE to meet the Ca2+ requirements of specific subcellular contact sites.

molecular biology↗