Evidence that alpha-synuclein functions as a negative regulator of Ca(++)-dependent alpha-granule release from human platelets.
alpha-Synuclein has been implicated in the pathogenesis of Parkinson disease (PD) and related neurodegenerative disorders. More recently, it has been suggested to be an important regulatory component of vesicle transport in neuronal cells. alpha-Synuclein is also highly expressed in platelets and is loosely associated with the membrane of the secretory alpha-granules. However, the functional significance of these observations is unknown. In this study, the possible function of alpha-synuclein in vesicle transport, with particular regard to alpha-granule release from the platelets, was investigated. The results showed that ionomycin- or thrombin-induced alpha-granule secretion was inhibited by exogenous alpha-synuclein addition in a dose-dependent manner. However, [(3)H]5-HT release from the dense granules and hexosaminidase release from the lysosomal granules were not affected. Two point mutants (A30P and A53T) found in some familial types of PD, in addition to beta-synuclein and alpha-synuclein112, effectively inhibited PF4 release from the alpha-granules. However, the deletion mutants, which completely lacked either the N-terminal region or the C-terminal tail, did not affect alpha-granule release. Interestingly, exogenously added alpha-synuclein appeared to enter the platelets but did not change the Ca(++) level in the platelets at the resting state and the increase in the Ca(++) level on stimulation. Electron microscopy also supported that alpha-synuclein inhibits alpha-granule release. These results suggest that alpha-synuclein may function as a specific negative regulator of alpha-granule release in platelets.
Park
Sang Myun
SM
Department of Microbiology and Brain Korea 21 Project of Medical Sciences, Department of Clinical Pathology, and Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
Jung
Han Young
HY
Kim
Hyun Ok
HO
Rhim
Hyangshuk
H
Paik
Seung R
SR
Chung
Kwang Chul
KC
Park
Jeon Han
JH
Kim
Jongsun
J
D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D002118:Calcium / Q000097:blood*; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000503:physiopathology; D017354:Point Mutation; D011994:Recombinant Proteins / Q000494:pharmacology; D051843:Synucleins; D013917:Thrombin / Q000494:pharmacology; D051844:alpha-Synuclein; D051846:beta-Synuclein
D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497607:SNCB protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D015759:Ionomycin; D013917:Thrombin; D002118:Calcium