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
Frank P
FP
Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Soehn
Anne S
AS
Berg
Daniela
D
Melle
Christian
C
Schiesling
Carola
C
Lang
Mira
M
Kautzmann
Sabine
S
Strauss
Karsten M
KM
Franck
Thomas
T
Engelender
Simone
S
Pahnke
Jens
J
Dawson
Simon
S
von Eggeling
Ferdinand
F
Schulz
Jörg B
JB
Riess
Olaf
O
Krüger
Rejko
R
D000074183:ATPases Associated with Diverse Cellular Activities; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D016631:Lewy Bodies; D008247:Lysosomes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000209:etiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism* / Q000502:physiology
D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C118958:SNCAIP protein, human; C088863:PSMC4 protein, human; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities