Biology subjects

Sivertsen, M. v. T.

Publications and source records attributed to Sivertsen, M. v. T..

2 recordsLinked to original sources

bioRxiv2025

Familial Alzheimer disease mutation identifies novel role of SORLA in release of neurotrophic exosomes

Sortilin-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor that directs target proteins between endocytic and secretory compartments of cells. Mutations in SORL1, encoding SORLA, are common in individuals suffering from Alzheimer disease (AD) of unknown etiology. Conceptually, characterization of inheritable SORL1 variants associated with AD can provide important new information about functions of this receptor relevant for aging brain health. Here, we focused on elucidation of the AD-associated variant SORLA N1358S, carrying a mutation in the main ligand binding domain of the receptor. Using unbiased quantitative proteome screens, we identified major alterations in the mutant receptor interactome linked to biogenesis and secretion of exosomes. Using advanced biophysical, cell biological, as well as functional studies in stem cell-derived human cell models we corroborated impaired release and loss of neurotrophic action of exosomes from neurons and microglia expressing SORLAN1358S. An impaired neurotrophic potential was attributed to an altered exosomal content of RNA binding proteins and associated microRNAs, known to control neuronal growth and maturation. Our studies identified a so far unknown function for SORLA in controlling the quantity and trophic quality of extracellular vesicles secreted by cells, and they argue for impaired cellular cross talk through exosomes as a pathological trail contributing to the risk of AD seen with carriers of SORL1 variants.

neuroscience↗

bioRxiv2023

Microplate Format Protein Nanopatterning for High-Throughput Screening of Cellular Microenvironments

An advanced protein nanopatterned cell culture platform is engineered to emulate the extracellular matrixs complexity, enabling precise nanoscale biomolecule copatterning to mimic environments analogous to native tissue for cellular assays. Nanopatterns fabricated through sparse colloidal lithography, with 100 nm to 800 nm features in separate wells, are seamlessly integrated into standard microplate formats (96-well/384-well). Robust patterns are built from fully PEGylated, passivated thin glass coverslips optimized for minimal nonspecific interactions. Biotin-avidin binding and click chemistry to ensure the accurate and robust localization of bioligands. The transparent, metal-free substrates are free of topographical interference, rendering them ideal for diverse fluorescence microscopy techniques encompassing single-molecule TIRFM and extensive high-throughput imaging. The structural stability of these nanopatterns persists beyond a year in storage and long-term in cell culture conditions, endorsing their application for prolonged experimental studies and potential for widespread academic and industrial use. The platform has been demonstrated for nanopatterning an array of biomolecules, from small molecules to proteins, DNA, and extracellular matrix components, instrumental for studying cell signaling. Experiments with C2C12 cells demonstrated the exceptional specificity of the nanopatterned microplates, with nonspecific adhesion remaining below 2% and the platforms ability to elicit size-dependent cellular reactions when interfaced with nanopatterned fibronectin.

bioengineering↗