α-Synuclein condensation in synaptic vesicle function and synucleinopathies
Dan Li1, Kaien Liu2, Danni Li3
1Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
Trends in Cell Biology
|April 30, 2025
Summary
Alpha-synuclein (α-syn) interactions with synaptic vesicles (SVs) are vital for normal brain function. Disruptions in these interactions drive neurodegeneration and synaptic dysfunction, offering therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alpha-synuclein (α-syn) plays a critical role in synaptic vesicle (SV) function.
- Liquid-liquid phase separation (LLPS) of α-syn involving SVs is essential for physiological processes.
- Dysregulation of α-syn-SV interactions is implicated in neurodegenerative diseases.
Purpose of the Study:
- To review the functional interactions between α-syn and SVs in physiological and pathological states.
- To explore the role of α-syn condensation in synaptic function and dysfunction.
- To discuss therapeutic strategies targeting α-syn-SV interactions.
Main Methods:
- Literature review of studies on α-synuclein and synaptic vesicles.
- Analysis of research on liquid-liquid phase separation (LLPS) of α-syn.
- Examination of pathological mechanisms in neurodegeneration.
Main Results:
- α-syn's condensation state influences its interaction with SVs.
- Pathological conditions disrupt α-syn-SV interactions, leading to aggregation and synaptic dysfunction.
- Targeting α-syn-SV interactions shows therapeutic potential.
Conclusions:
- α-syn has a dual role: regulating SVs physiologically and driving neurodegeneration pathologically.
- Understanding α-syn-SV dynamics is key to developing treatments for neurodegenerative disorders.
- Modulating α-syn-SV interactions may restore synaptic function.
Related Concept Videos
03:03Amyloid Fibrils
9.0K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
9.0K
01:26Fusion of Secretory Vesicles with the Plasma Membrane
9.5K
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...
In 1993, Jim Rothman proposed that the antiparallel pairing of vesicular and transmembrane SNAREs, or...
9.5K
01:43SNAREs and Membrane Fusion
9.3K
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...
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...
9.3K
01:22Lysosomal Hydrolases
3.7K
Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
3.7K
01:33Overview of Secretory Vesicles
7.2K
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...
Various proteins regulate the aggregation of molecules inside the secretory vesicles. Chromogranins...
7.2K
01:26Chemical Synapses
8.5K
Chemical synapses are specialized sites between two neurons or between a neuron and a non-neuronal cell like a muscle, glandular or sensory cell.
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is...
8.5K