alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells.
alpha-Synuclein has been implicated in the pathogenesis of many neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Although the function of alpha-synuclein remains largely unknown, recent studies have demonstrated that this protein can interact with phospholipids. To address the role of alpha-synuclein in neurodegenerative disease, we have investigated whether it binds phospholipase D (PLD) and affects PLD activity in human embryonic kidney (HEK)-293 cells overexpressing wild type alpha-synuclein or the mutant forms of alpha-synuclein (A53T, A30P) associated with Parkinson's disease. Tyrosine phosphorylation of alpha-synuclein appears to play a modulatory role in the inhibition of PLD, because mutation of Tyr(125) to Phe slightly increases inhibitory effect of alpha-synuclein on PLD activity. Treatment with pervanadate or phorbol myristate acetate inhibits PLD more in HEK 293 cells overexpressing alpha-synuclein than in control cells. Binding of alpha-synuclein to PLD requires phox and pleckstrin homology domain of PLD and the amphipathic repeat region and non-Abeta component of alpha-synuclein. Although biologically important, co-transfection studies indicate that the interaction of alpha-synuclein with PLD does not influence the tendency of alpha-synuclein to form pathological inclusions. These results suggest that the association of alpha-synuclein with PLD, and modulation of PLD activity, is biologically important, but PLD does not appear to play an essential role in the pathophysiology of alpha-synuclein.
Ahn
Bong-Hyun
BH
Department of Physiology, Research Institute of Molecular Genetics, and Anatomy, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Rhim
Hyangshuk
H
Kim
Shi Yeon
SY
Sung
Young-Mo
YM
Lee
Mun-Yong
MY
Choi
Ju-Youn
JY
Wolozin
Benjamin
B
Chang
Jong-Soo
JS
Lee
Young Han
YH
Kwon
Taeg Kyu
TK
Chung
Kwang Chul
KC
Yoon
Shin-Hee
SH
Hahn
Sang June
SJ
Kim
Myung-Suk
MS
Jo
Yang-Hyeok
YH
Min
Do Sik
DS
D000818:Animals; D001798:Blood Proteins / Q000737:chemistry; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D010739:Phospholipase D / Q000737:chemistry* / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051843:Synucleins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology*; D051844:alpha-Synuclein
D001798:Blood Proteins; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; C076715:pervanadate; C039077:platelet protein P47; D014638:Vanadates; D014443:Tyrosine; D005982:Glutathione Transferase; D010739:Phospholipase D; D013755:Tetradecanoylphorbol Acetate