Extracellular vesicle homeostasis in health and disease

• Applicant: Professor Dr. Andreas Neueder
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553092974

Extracellular vesicles (EVs) are secreted by most, if not all cells. They are composed of lipids, proteins, RNAs and other small molecules and are generally categorized into three subtypes: Exosomes, ectosomes and apoptotic bodies. These differ in their biogenesis and approximate size. EVs transfer information from one cell to another by fusing with the recipient cell releasing proteins, RNAs and other molecules. Since all EVs are generated with material from the secreting cell, analysis of their composition potentially allows insights into the molecular state of these cells. Interestingly, EVs can cross the blood brain barrier and thus might also help to gain insights into pathological processes within the central nervous system (CNS). We have recently analysed multiple tissues and cell lines of more than 60 participants of Huntington disease, a devastating neurodegenerative disorder, with a multi-omics panel under the MTM HD study. The study included unaffected individuals and HD patients before or shortly after symptom onset. Strikingly, the most consistent phenotype across different sample sources was an observed dysregulation of EV biology in the HD patients. When we analysed protein modifications in the proteomics dataset of the plasma EVs, we detected extensive modifications independent of the HD status, i.e. also in the EVs isolated from healthy individuals. The massive number of very specific protein modifications in the proteomics data led us to the following hypothesis: We picture the role of the modifications similar to the effect of E3-ubiquitin ligases, which generate the signal for protein targeting to diverse pathways depending on the nature of the ubiquitin chain, e.g. linear vs. branched. Only in this case, a "EV-modification-code" designates proteins for loading into EVs, or potentially recycling through the endosome system, etc. We plan to disrupt potential enzymes responsible for the modifications and analyse the protein modification status of EV associated proteins, EV loadings and disruptions of the modifications in disease conditions. As described above, EVs are attractive candidates for a glimpse into the CNS through analysis of the cerebrospinal fluid (CSF) EVs. We will analyse the protein modification status of CSF EVs in health and disease. Furthermore, we will use primary human cell lines to analyse the EV signatures of individual cell types of the CNS - neurons, astrocytes, oligodendrocytes, microglia and choroid plexus epithelial cells. We think that this dataset will help to deconvolute the bulk CSF EV signal. Clinical intervention would ideally target a specifically affected cell/neuronal population. Hence our strategy, if successful, will provide an immense benefit of a direct readout of the neuronal health state from CSF EVs.

• DFG Programme: Research Grants