Cholesterol in Synaptic Vesicle Membranes Regulates the Vesicle-Binding, Function, and Aggregation of α-Synuclein

The formation of small vesicles is mediated by cytoplasmic coats the assembly of which is regulated by the activity of GTPases, kinases, and phosphatases. A heterotetrameric AP-3 adaptor complex has been implicated in the formation of synaptic vesicles from PC12 endosomes ( Faundez et al., 1998 ). When the small GTPase ARF1 is prevented from hydrolyzing GTP, we can reconstitute AP-3 recruitment to synaptic vesicle membranes in an assembly reaction that requires temperatures above 15°C and the presence of ATP suggesting that an enzymatic step is involved in the coat assembly. We have now found an enzymatic reaction, the phosphorylation of the AP-3 adaptor complex, that is linked with synaptic vesicle coating. Phosphorylation occurs in the β3 subunit of the complex by a kinase similar to casein kinase 1α. The kinase copurifies with neuronal-specific AP-3. In vitro, purified casein kinase I selectively phosphorylates the β3A and β3B subunit at its hinge domain. Inhibiting the kinase hinders the recruitment of AP-3 to synaptic vesicles. The same inhibitors that prevent coat assembly in vitro also inhibit the formation of synaptic vesicles in PC12 cells. The data suggest, therefore, that the mechanism of AP-3-mediated vesiculation from neuroendocrine endosomes requires the phosphorylation of the adaptor complex at a step during or after AP-3 recruitment to membranes.

Download Full-text

Ion channels on synaptic vesicle membranes studied by planar lipid bilayer method

Biophysical Journal ◽

10.1016/s0006-3495(92)81731-9 ◽

1992 ◽

Vol 63 (6) ◽

pp. 1500-1505 ◽

Cited By ~ 13

Author(s):

M. Sato ◽

K. Inoue ◽

M. Kasai

Keyword(s):

Ion Channels ◽

Synaptic Vesicle ◽

Lipid Bilayer ◽

Planar Lipid Bilayer ◽

Vesicle Membranes

Download Full-text

Lipids: Key Players That Modulate α-Synuclein Toxicity and Neurodegeneration in Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21093301 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3301 ◽

Cited By ~ 5

Author(s):

Akio Mori ◽

Yuzuru Imai ◽

Nobutaka Hattori

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Synaptic Vesicle ◽

Dopaminergic Neurons ◽

Vesicle Membranes ◽

Synaptic Functions ◽

Aggregation Processes ◽

Lipid Interaction ◽

Altered Lipid

Parkinson’s disease (PD) is the second most common neurodegenerative disease; it is characterized by the loss of dopaminergic neurons in the midbrain and the accumulation of neuronal inclusions, mainly consisting of α-synuclein (α-syn) fibrils in the affected regions. The prion-like property of the pathological forms of α-syn transmitted via neuronal circuits has been considered inherent in the nature of PD. Thus, one of the potential targets in terms of PD prevention is the suppression of α-syn conversion from the functional form to pathological forms. Recent studies suggested that α-syn interacts with synaptic vesicle membranes and modulate the synaptic functions. A series of studies suggest that transient interaction of α-syn as multimers with synaptic vesicle membranes composed of phospholipids and other lipids is required for its physiological function, while an α-syn-lipid interaction imbalance is believed to cause α-syn aggregation and the resultant pathological α-syn conversion. Altered lipid metabolisms have also been implicated in the modulation of PD pathogenesis. This review focuses on the current literature reporting the role of lipids, especially phospholipids, and lipid metabolism in α-syn dynamics and aggregation processes.

Download Full-text