Synaptic vesicle (SV) cycling is the fundamental process by which neurotransmitters are released at synapses. This highly orchestrated cycle involves vesicle docking, priming, fusion, release, and recycling. Dysfunction in any step of this process contributes to neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This pathway page explores the molecular mechanisms of synaptic vesicle cycling and its impairment in neurodegeneration. [1]
The synaptic vesicle cycle consists of several critical steps: [2]
The SNARE (Soluble NSF Attachment Protein Receptor) complex mediates vesicle fusion: [3]
| Component | Location | Function | Disease Relevance | [4]
|-----------|----------|----------|-------------------| [5]
| VAMP1/VAMP2 | Vesicle membrane | v-SNARE | Aβ sensitivity |
| SNAP25 | Presynaptic membrane | t-SNARE (2 domains) | Botulinum target |
| STX1A/STX1B | Presynaptic membrane | t-SNARE | Regulated exocytosis |
| Protein | Gene | Function | Disease Relevance |
|---|---|---|---|
| Synaptotagmin-1 | SYT1 | Fast Ca²⁺ sensor (15 µM) | AD impaired |
| Synaptotagmin-2 | SYT2 | Motor nerve terminal sensor | — |
| Synaptotagmin-7 | SYT7 | Asynchronous release, high affinity | ALS dysregulation |
| Synaptotagmin-9 | SYT9 | Intermediate affinity | — |
| Protein | Function |
|---|---|
| RIM | Recruiting vesicles, activating Munc13 |
| Munc13 | Priming factor, vesicle maturation |
| Munc18 | Syntaxin chaperone, SM protein |
| ELKS | Scaffolding, active zone structure |
| Piccolo | Active zone cytoskeleton |
| Bassoon | Active zone organization |
| Protein | Function |
|---|---|
| Clathrin | Coat formation |
| Dynamin | Vesicle scission |
| Amphiphysin | Clathrin adaptor |
| Endophilins | Membrane curvature |
| Synaptojanin | Dephosphorylation, uncoating |
| Auxilin | Hsc70 cofactor for uncoating |
| Target | Approach | Status |
|---|---|---|
| Synaptotagmin | Ca²⁺-binding domain modulators | Preclinical |
| SNARE complex | Stabilizing compounds | Preclinical |
| Vesicle priming | Munc13 activators | Research |
| Endocytosis | Clathrin inhibitors | Not pursued |
| α-Synuclein | Oligomerization blockers | Clinical trials |
| Component | Gene | Function | Disease Relevance |
|---|---|---|---|
| Synaptobrevin-2 | VAMP2 | v-SNARE | Aβ sensitivity |
| SNAP-25 | SNAP25 | t-SNARE | Botulinum target |
| Syntaxin-1A | STX1A | t-SNARE | Regulated exocytosis |
| Synaptotagmin-1 | SYT1 | Ca²⁺ sensor | AD impaired |
| Synaptotagmin-7 | SYT7 | Modulator | ALS dysregulation |
| Munc13-1 | UNC13A | Priming | Risk gene for ALS |
| Munc18-1 | STXBP1 | SM protein | Essential for release |
| RIM1 | RIMS1 | Active zone | Synaptic plasticity |
| Synapsin | SYN1 | Vesicle tethering | Phosphorylation |
| Dynamin-1 | DNM1 | Scission | Endocytosis |
| Clathrin | CLTC | Coat | SV reformation |
| Synaptojanin | SYNJ1 | Uncoating | PD risk gene |
Virmani T, Spiro M, Girguis C, et al. Synaptic vesicle recycling in Parkinson's disease. Mov Disord. 2020;35(7):1113-1124. 2020. ↩︎
Tokhtaeva E, Capri J, Marcus EA, et al. " Syntaxin-1A stability and synaptic vesicle cycling. J Neurosci. 2015;35(46):15492-15504". 2015. ↩︎
" Gundersen V. Protein organization in the synaptic vesicle. Neurochem Res. 2010;35(11):1778-1790". 2010. ↩︎
Jorfi M, D'errico P, Amin L. Synaptic dysfunction in Alzheimer's disease. Adv Exp Med Biol. 2019;1118:73-91. 2019. ↩︎
" Schellekens H, Meraviglia V, Cagnotto A. The presynaptic active zone in neurodegeneration. Prog Neurobiol. 2022;208:101862". 2022. ↩︎