HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: fj.06-6734comv1 21/8/1759    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marx, F. P. Articles by Krüger, R. Search for Related Content PubMed PubMed Citation Articles by Marx, F. P. Articles by Krüger, R.

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

Frank P. Marx^*, Anne S. Soehn, Daniela Berg^*,, Christian Melle, Carola Schiesling^*, Mira Lang^*, Sabine Kautzmann^*, Karsten M. Strauss^*, Thomas Franck, Simone Engelender, Jens Pahnke^||, Simon Dawson^¶, Ferdinand von Eggeling, Jörg B. Schulz^*,1, Olaf Riess and Rejko Krüger^*,2

^* Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany;

Department of Medical Genetics, University of Tübingen, Tübingen, Germany;

Department of Pharmacology, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel;

Core Unit Chip Application, Institute of Human Genetics and Anthropology, Friedrich-Schiller-University, Jena, Germany;

^|| Department of Pathology, Neuropathologic Institute, University Hospital Zürich, Zürich, Switzerland; and

^¶ School of Biomedical Sciences, University of Nottingham, Nottingham, UK

²Correspondence: Laboratory of Functional Neurogenomics, Center of Neurology and Hertie-Institute for Clinical Brain Research, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. E-mail: rejko.krueger{at}uni-tuebingen.de

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., Krüger, R. The proteasomal subunit S6 ATPase is a novel synphilin-1 interacting protein—implications for Parkinson’s disease.

Key Words: neurodegeneration • ubiquitin • alpha-synuclein • proteasome

This article has been cited by other articles:

				N. Zaarur, A. B. Meriin, V. L. Gabai, and M. Y. Sherman Triggering Aggresome Formation: DISSECTING AGGRESOME-TARGETING AND AGGREGATION SIGNALS IN SYNPHILIN 1 J. Biol. Chem., October 10, 2008; 283(41): 27575 - 27584. [Abstract] [Full Text] [PDF]