Proteinopathy in inflammatory neurodegeneration

• Applicant: Professor Dr. Manuel A. Friese
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321760974

• Final Report Year: 2024

Final Report Abstract

In this project we explored pathological changes in the neuronal proteome during neuroinflammation. Based on our findings that the protein Bassoon forms toxic accumulations in neuronal somata during neuroinflammation, we explored the pathogenic potential of the Bassoon mutation P3882A using a newly generated genetic mouse model. Moreover, we generated a Bassoon-eGFP knockin mouse to facilitate the subcellular imaging and immunoprecipitation of endogenous Bassoon. Furthermore, we explored the utility of Bassoon as a serum biomarker of neurodegeneration in individuals with MS. Finally, we conducted a neuron-specific proteome screening during neuroinflammation to identify pathological proteome changes beyond Bassoon. We discovered a disturbed ubiquitin proteasome system in neurons as contributing factor for protein accumulations. Taken together, we generated valuable molecular tools for the investigation of Bassoon in the context of neuronal pathologies, established Bassoon as a serum biomarker for inflammatory neurodegeneration and identified novel neuronal candidate proteins that potentially contribute to proteome dysregulation during neuroinflammation.

Publications

• G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis. Science Advances, 8(31).
  Rothammer, Nicola; Woo, Marcel S.; Bauer, Simone; Binkle-Ladisch, Lars; Di Liberto, Giovanni; Egervari, Kristof; Wagner, Ingrid; Haferkamp, Undine; Pless, Ole; Merkler, Doron; Engler, Jan Broder & Friese, Manuel A.
  
• Identification of early neurodegenerative pathways in progressive multiple sclerosis. Nature Neuroscience, 25(7), 944-955.
  Kaufmann, Max; Schaupp, Anna-Lena; Sun, Rosa; Coscia, Fabian; Dendrou, Calliope A.; Cortes, Adrian; Kaur, Gurman; Evans, Hayley G.; Mollbrink, Annelie; Navarro, José Fernández; Sonner, Jana K.; Mayer, Christina; DeLuca, Gabriele C.; Lundeberg, Joakim; Matthews, Paul M.; Attfield, Kathrine E.; Friese, Manuel A.; Mann, Matthias & Fugger, Lars
  
• The neuropathobiology of multiple sclerosis. Nature Reviews Neuroscience, 25(7), 493-513.
  Woo, Marcel S.; Engler, Jan Broder & Friese, Manuel A.