Fluorescence Studies Suggest a Role for α-Synuclein in the Phosphatidylinositol Lipid Signaling Pathway

Abstract

Alpha-synuclein plays a key role in the pathogenesis of many neurodegenerative diseases. To date, its cellular role has yet to be determined, although it has been proposed to be connected to calcium and G protein-mediated dopamine signaling. Alpha-synuclein is known to bind strongly to model membrane surfaces where it may interact with other membrane-associated proteins. Here, we find that the membrane association of alpha-synuclein is enhanced by the presence of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)] and Ca(2+). We also find that alpha-synuclein interacts with high affinity with the G protein-regulated enzyme phospholipase Cbeta(2) (PLCbeta(2)), which catalyzes the hydrolysis of PI(4,5)P(2). Binding of alpha-synuclein to PLCbeta(2) reduces its catalytic activity by 50%, but causes its level of activation by Gbetagamma subunits to increase from 4- to 24-fold. This effect is greatly reduced for A53T alpha-synuclein, which is a mutant associated with familial Parkinson's disease. PI(4,5)P(2) hydrolysis by PLCbeta(2) results in an increase in the intracellular Ca(2+) concentration, and we find that in cultured cells the presence of alpha-synuclein results in a 6-fold enhancement in the release of Ca(2+) from intracellular stores in response to agents that release Gbetagamma subunits relative to controls. Alpha-synuclein also enhances the increase in the level of inositol phosphates seen upon G protein stimulation, suggesting that it also may interact with PLCbeta(2) in cells. Given that Ca(2+) and dopamine regulation are mediated through PLCbeta and G protein signals, our results suggest that alpha-synuclein may play a role in inositol phospholipid signaling.

Mitochondrial Lipid Abnormality and Electron Transport Chain Impairment in Mice Lacking α-Synuclein

“…These structural similarities suggest that ␣-synuclein could serve as an intracellular functional equivalent of apolipoproteins in the brain and so similarly may function in binding and intracellular transport of lipids, stabilizing membranes, and regulating lipid metabolism. Results to support this hypothesis include the observations that ␣-synuclein alters both phospholipase C and D activities in vitro, while its inhibitory effect on phospholipase D may be regulated by ␣-synuclein phosphorylation (31,49,52). Additionally, ␣-synuclein binds to phospholipid vesicles containing stored triglycerides in cultured cells and protects them from hydrolysis (12), suggesting that ␣-synuclein may have a role in stabilizing lipid membrane.…”

Mechanistic aspects of Parkinson’s disease: α-synuclein and the biomembrane

“…Thus, the synucleins may be involved in the regulation of vesicle recycling and in the maintenance of dopamine homeostasis. A link with inositol-mediated intracellular calcium signalling was recently established when it was shown that aS binds with high affinity to membranes containing phosphatidylinositol-4,5-bisphosphate and that it modulates the activity of phospholipase-Cb [133]. Regarding the critical role of calcium signalling in central cellular events, such as vesicle trafficking and dopamine uptake, this finding deserves further research to elucidate its meaning within the framework of synaptic neurotransmission.…”

Molecular Insights into the Interaction between α-Synuclein and Docosahexaenoic Acid

“…[16][17][18] In addition, the protein exhibits an inhibitory activity of phospholipase D both in vitro and in vivo, indicating a role in lipid-mediated signal transduction. 19 α-Syn seems to interact with unsaturated and polyunsaturated fatty acids (PUFAs), but whether this interaction involves free FAs, as in the case of FA binding proteins 20 or micelles, 21,22 has not been elucidated yet. This interaction promotes the oligomerization of α-syn.…”