The proteasomal subunit S6 ATPase is a novel synphilin-1 interacting protein -: implications for Parkinson's disease

Synphilin-1 is linked to Parkinson's disease ( PD), based on its role as an alpha-synuclein (PARK1)-interacting protein and substrate of the ubiquitin E3 ligase Parkin (PARK2) and because of its presence in Lewy bodies ( LB) in brains of PD patients. We found that overexpression of synphilin-1 in cells leads to the formation of ubiquitinated cytoplasmic inclusions supporting a derangement of the ubiquitin-proteasome system in PD. We report here a novel specific interaction of synphilin- 1 with the regulatory proteasomal protein S6 ATPase ( tbp7). Functional characterization of this interaction on a cellular level revealed colocalization of S6 and synphilin- 1 in aggresome- like intracytoplasmic inclusions. Overexpression of synphilin- 1 and S6 in cells caused reduced proteasomal activity associated with a significant increase in inclusion formation compared to cells expressing synphilin-1 alone. Steady-state levels of synphilin-1 in cells were not altered after cotransfection of S6 and colocalization of synphilin-1-positive inclusions with lysosomal markers suggests the presence of an alternative lysosomal degradation pathway. Subsequent immunohistochemical studies in brains of PD patients identified S6 ATPase as a component of LB. This is the first study investigating the physiological role of synphilin- 1 in the ubiquitin proteasome system. Our data suggest a direct interaction of synphilin- 1 with the regulatory complex of the proteasome modulating proteasomal function.-Marx, F. P., Soehn, A. S., Berg, D., Melle, C., Schiesling, C., Lang, M., Kautzmann, S., Strauss, K. M., Franck, T., Engelender, S., Pahnke, J., Dawson, S., von Eggeling, F., Schulz, J. B., Riess, O., Kruger, R. The proteasomal subunit S6 ATPase is a novel synphilin-1 interacting protein-implications for Parkinson's disease.