RP8: The neuronal interactome of mitochondrial m-AAA proteases

• Antragsteller: Professor Dr. Thomas Langer
• Fachliche Zuordnung: Molekulare Biologie und Physiologie von Nerven- und Gliazellen
• Förderung: Förderung von 2010 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 35615435

Neurodegenerative disorders are often associated with a dysfunction of mitochondria, illustrating essential functions of mitochondria for neuronal survival. Mutations in m-AAA proteases, ATP-dependent proteolytic complexes in the inner membrane of mitochondria, cause distinct neurodegenerative disorders, but the molecular basis of these deficiencies are not understood. Studies in yeast identified crucial functions of m- AAA proteases for protein quality control and for the regulation of mitochondrial morphology and ribosome biogenesis. Here, we will define the neuronal interactome of m-AAA proteases, in order to identify critical substrates and cofactors that are required for neuronal maintenance. Transgenic mouse lines will be established allowing the inducible and tissue-specific expression of proteolytically inactive and dominant negative variants of m-AAA protease subunits using Cre-mediated recombination. Proteins copurifying with m-AAA protease complexes isolated from different regions of the brain will be identified and functionally characterized. Moreover, we will identify neuronal proteins processed by the m-AAA protease by determining the N-proteome of murine brain mitochondria isolated from wild type and m-AAA protease-deficient mice by mass spectrometry.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 885: Neuronal Protein Turnover