Molecular mechanisms of pathogenic misfolding of α-synuclein

Coordinator:		Prof. Dr. Markus Zweckstetter, Prof. Dr. Jörg B. Schulz
Institution:		Max Planck Institut für Biophysikalische Chemie
Homepage:		www.mpibpc.mpg.de/de/zweckstetter

Enhanced expression of α-Synuclein (α-Syn) causes Parkinson´s disease (PD). We used a genetic screen in Drosophila to identify genes that enhance aSyn-induced toxicity when mutated. In this screen, we identified the mitochondrail Chaperon TRAP1. Reduction of TRAP1 enhances, whereas overexpression of human TRAP1 rescued αSyn-induced toxicity (loss of dopaminergic neurons). Moreover we were able to show that loss of TRAP1 enhances sensitivity towards oxidative stress. These results were not restricted to flies but could be transferred to human cells. Expression of αSyn in neuronal cells (SH-SY5Y) causes the fragmentation of otherwise tubular mitochondira. This effect can be ameliorated by TRAP1. These findings are helpful to clarify the etiology of PD. Loss-of-function mutations in the genes coding PINK1 and Parkin cause PD. PINK1 is localized in mitochondria and protects them from oxidative stress in a TRAP1 dependent manner. We were able to show that TRAP1 is able to compensate a PINK1 deficiency. Also these finding are not restricted to flies, but can recapitulated in human cells. Detrimental effects observed in PINK1 deficient SH-SY5Y cells can be rescued by TRAP1. PINK1 and Parkin are essential for mitochondrial quality control. PINK1 and Parkin participate in the recognition and degradation of dysfuctional mitochondria. We were able to show that in addition to the PINK1/Parkin pathway, there seems an additional, TRAP1 dependent way to protect cells from dysfunctional mitochondria. Our data clearly show that TRAP1 can compensate PINK1 but not Parkin deficiency. Further analysis implied that TRAP1 does not participate in mitochondrial quality control but acts further upstream to maintain mitochonrdrial function.