Contact Us

VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates

Affiliations
  • 1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 2Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
  • 3Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
  • 4University of Chinese Academy of Sciences, Beijing, China.
  • 5Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 6Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
  • 7State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 8Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
  • 9Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. lidan2017@sjtu.edu.cn.
  • 10Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China. lidan2017@sjtu.edu.cn.
  • 11Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA. jiajie.diao@uc.edu.

Published on:

July 1, 2024

Abstract

α-Synuclein (α-Syn) aggregation is closely associated with Parkinson’s disease neuropathology. Physiologically, α-Syn promotes synaptic vesicle (SV) clustering and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly. However, the underlying structural and molecular mechanisms are uncertain and it is not known whether this function affects the pathological aggregation of α-Syn. Here we show that the juxtamembrane region of vesicle-associated membrane protein 2 (VAMP2)-a component of the SNARE complex that resides on SVs-directly interacts with the carboxy-terminal region of α-Syn through charged residues to regulate α-Syn’s function in clustering SVs and promoting SNARE complex assembly by inducing a multi-component condensed phase of SVs, α-Syn and other components. Moreover, VAMP2 binding protects α-Syn against forming aggregation-prone oligomers and fibrils in these condensates. Our results suggest a molecular mechanism that maintains α-Syn’s function and prevents its pathological amyloid aggregation, the failure of which may lead to Parkinson’s disease.

Related Concept Videos

JoVE Research Video for Fusion of Secretory Vesicles with the Plasma Membrane 01:26

5.3K

Proteins and neurotransmitters in secretory vesicles can be released from a cell upon vesicle docking, priming, and fusion with the plasma membrane. Vesicles are docked and primed in preparation for the quick exocytosis of their contents in response to a stimulus. The fusion process is mainly carried out by a SNAP Receptor or SNARE complex, consisting of synaptobrevin, syntaxin-1, and SNAP-25.
In 1993, Jim Rothman proposed that the antiparallel pairing of vesicular and transmembrane SNAREs, or…

JoVE Research Video for SNAREs and Membrane Fusion 01:43

5.0K

Once a transport vesicle has recognized its target organelle, the vesicular membrane needs to fuse with the target membrane to unload the cargo. Transmembrane proteins called SNAREs present on organelle membranes and their vesicles, mediate vesicle fusion.
SNAREs exist in pairs that symmetrically interact and catalyze the fusion of the lipid bilayers in vesicle and target organelle. v-SNARE in the vesicle membrane are single polypeptide chains that bind to a complementary t-SNARE, composed of 2…

JoVE Research Video for Clathrin Coated Vesicles 01:12

5.9K

Clathrin-coated vesicles use endocytosis to transport receptors and lysosomal hydrolases from the Golgi to the lysosome in the late secretory pathway. Clathrin-mediated endocytosis was the first described endocytic process, and Clathrin-coated vesicles remain one of the most well-studied transport vesicles. The molecular machinery that generates clathrin-coated vesicles comprises over 50 proteins that precisely coordinate vesicle formation. Cell surface receptors concentrated in indented sites…

JoVE Research Video for Vesicular Tubular Clusters 01:45

2.2K

After budding out from the ER membrane, some COPII vesicles lose their coat and fuse with one another to form larger vesicles and interconnected tubules called vesicular tubular clusters or VTCs. These clusters constitute a compartment at the ER-Golgi interface known as ERGIC (Endoplasmic Reticulum Golgi Intermediate Compartment). The ERGIC is a mobile membrane-bound cargo transport system that sorts proteins secreted from ER and delivers them to the Golgi.
With the help of motor proteins such…

JoVE Research Video for Overview of Secretory Vesicles 01:33

3.2K

Secretory vesicles, also known as dense core vesicles (DCVs), are membrane-bound vesicles that transport secretory proteins, such as hormones or neurotransmitters. Regulated secretory vesicles transport proteins from the trans-Golgi network to the exterior of the cell. Proteins present in regulated secretory vesicles are required to be rapidly exocytosed in large amounts upon a specific stimulus.
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins…

JoVE Research Video for Golgi Matrix Proteins 01:12

1.9K

Golgi matrix proteins are a group of highly dynamic proteins that maintain the stacked structure of Golgi. These proteins adapt to rapid morphological changes of the Golgi during the cell cycle. During cell division, mild proteolysis removes these connections resulting in Golgi unstacking. In The daughter cells, these proteins help reassemble the unstacked Golgi.
One of the first identified Golgi matrix proteins was GM130, a rod-like protein located in the cis-Golgi. Subsequently, many Golgi…