SEP 21, 2022 9:00 AM PDT

A Physiologic Role of α-Synuclein in Synaptic Vesicle Recycling

Presented at: Cell Biology 2022
C.E. Credits: P.A.C.E. CE Florida CE
Speaker

Abstract

α-synuclein (α-syn) is a small presynaptic protein linked to the pathogenesis of Parkinson’s disease (PD) and related disorders, collectively called synucleinopathies. Phosphorylation of α-syn at Ser-129 is a pathologic hallmark of synucleinopathies and is widely considered to be a therapeutic target. Using pHluorin assays, we and others have shown that modest levels of α-syn overexpression attenuates synaptic vesicle (SV) recycling, suggesting that α-syn is a physiologic attenuator of neurotransmitter release. Furthermore, we have shown that binding of α-syn to VAMP2 is necessary for α-syn-induced synaptic attenuation. In this study, we evaluated the presynaptic targeting of phospho-incompetent (Ser-129A) and phospho-mimic (Ser-129D) α-syn mutants, and also evaluated effects of Ser-129 phosphorylation on SV-recycling using pHluorins. While mimicking Ser129 phosphorylation augmented synaptic α-syn accumulation and further attenuated SV-recycling as expected, surprisingly, preventing Ser129-P completely blocked the ability of α-syn to attenuate SV-recycling; suggesting a physiologic role for this post-translational modification at synapses. Mechanistically, we found that phosphorylation at the Ser-129 site was required for α-syn binding to VAMP2 and subsequent synaptic attenuation, explaining the inability of Ser129 phospho-incompetent α-syn to attenuate SV-recycling. Finally, AlphaFold2-based modeling and membrane-binding simulations support a scenario where Ser-129 phosphorylation triggers a conformational change in α-syn that exposes its C-terminus, allowing VAMP2 binding and consequent functionality. Collectively, the data suggest a physiologic role for α-syn S129 phosphorylation and warrant caution in developing therapeutic agents that inhibit this phosphorylation site.

Learning Objectives:

1. Elucidate the importance of S129 phosphorylation of α-synuclein to physiology, in addition to its pathological association. 
 
2. Explain the mechanism by which α-synuclein S129site phosphorylation triggers synaptic vesicle recycling. 
 
3. Describe the current approaches to measure synaptic recycling as a result of neuronal activity. 


Show Resources
You May Also Like
OCT 13, 2022 9:00 AM +08
OCT 13, 2022 9:00 AM +08
First Broadcast: Date: October 12, 2022 Time: 8:00am PDT, 11:00am EDT Second Broadcast: Date: October 12, 2022 Time: 9:00am SGT The new Embedded CryoSPARC Live, now fully integrated with t...
AUG 10, 2022 10:00 AM PDT
AUG 10, 2022 10:00 AM PDT
Date: August 10, 2022 Time: 10:00am PDT, 1:00pm EDT The global pandemic has increased focus and scrutiny on molecular diagnostic assay development, resulting in a need for assays that provid...
AUG 24, 2022 7:00 AM PDT
AUG 24, 2022 7:00 AM PDT
Date: August 24, 2022 Time: 7:00am (PDT), 10:00pm (EDT), 4:00pm (CEST) Light field microscopy was first introduced in 2006, and allows users to capture the 4D light field within the microsco...
JUN 28, 2022 7:00 AM PDT
JUN 28, 2022 7:00 AM PDT
Date: June 28, 2022 Time: 3:00pm (BST), 4:00pm (CET), 9:00am (CST), 7am (PST) Light-sheet microscopy is an extremely versatile imaging technique with a vast range of implementations that are...
NOV 09, 2022 8:00 AM PST
C.E. CREDITS
NOV 09, 2022 8:00 AM PST
Date: November 09, 2022 Time: 8:00am (PST), 11:00am (EST), 5:00pm (CET) The field of cell and gene therapy is rapidly growing. In particular, the use of lentiviruses in CAR-T applications is...
JUN 21, 2022 6:00 AM PDT
JUN 21, 2022 6:00 AM PDT
Date: June 21, 2022 Time: 6:00am (PDT), 9:00am (EDT), 3:00pm (CEST) The global understanding and practice of medicine is currently undergoing a revolutionary change. This shift to precision...
Loading Comments...
Show Resources
Attendees