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- Title
LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α.
- Authors
Nadiminti, Sravanthi S. P.; Dixit, Shirley B.; Ratnakaran, Neena; Deb, Anushka; Hegde, Sneha; Boyanapalli, Sri Padma Priya; Swords, Sierra; Grant, Barth D.; Koushika, Sandhya P.
- Abstract
Synaptic vesicle proteins (SVps) are transported by the motor UNC-104/KIF1A. We show that SVps travel in heterogeneous carriers in C. elegans neuronal processes, with some SVp carriers co-transporting lysosomal proteins (SV-lysosomes). LRK-1/LRRK2 and the clathrin adaptor protein complex AP-3 play a critical role in the sorting of SVps and lysosomal proteins away from each other at the SV-lysosomal intermediate trafficking compartment. Both SVp carriers lacking lysosomal proteins and SV-lysosomes are dependent on the motor UNC-104/KIF1A for their transport. In lrk-1 mutants, both SVp carriers and SV-lysosomes can travel in axons in the absence of UNC-104, suggesting that LRK-1 plays an important role to enable UNC-104 dependent transport of synaptic vesicle proteins. Additionally, LRK-1 acts upstream of the AP-3 complex and regulates its membrane localization. In the absence of the AP-3 complex, the SV-lysosomes become more dependent on the UNC-104-SYD-2/Liprin-α complex for their transport. Therefore, SYD-2 acts to link upstream trafficking events with the transport of SVps likely through its interaction with the motor UNC-104. We further show that the mistrafficking of SVps into the dendrite in lrk-1 and apb-3 mutants depends on SYD-2, likely by regulating the recruitment of the AP-1/UNC-101. SYD-2 acts in concert with AP complexes to ensure polarized trafficking & transport of SVps. Author summary: Synaptic vesicles (SVs) at neuronal synapses have a defined membrane composition and size. We show that SV proteins (SVps) are transported in carriers with heterogenous composition, with a small subset containing lysosomal proteins (SV-lysosomes). We propose that the SV-lysosomes are perhaps post-Golgi trafficking intermediates from which the SV proteins are sorted away from lysosomal proteins through the action of LRK-1, the ortholog of LRRK2, which is associated with both familial and sporadic Parkinson's disease, and the AP-3 complex, which is associated with Hermansky-Pudlak syndrome. These sorting events could be necessary events for the formation of SV precursors. SVp carriers and SV-lysosomes both depend on the UNC-104/KIF1A kinesin motor and the active zone protein SYD-2/Liprin-α for their transport. However, in the absence of the AP-3 complex, altered trafficking of SV and lysosomal proteins likely causes the SV-lysosomes to become more dependent on the UNC-104-SYD-2 complex for their transport, while the SVp carriers lacking lysosomal proteins become partially independent of UNC-104. We therefore propose that SYD-2 can act as a link between the upstream trafficking events and the subsequent transport of SVps likely through its interaction with the motor UNC-104. We also show that SYD-2 genetically interacts with and regulates the localization of the AP-1 complex to facilitate polarised distribution of SVp carriers to axons. Thus, our study highlights novel roles for SYD-2 in several early steps of SVp trafficking.
- Subjects
AMPA receptors; COATED vesicles; SYNAPTIC vesicles; PARKINSON'S disease; ADAPTOR proteins; CARRIER proteins; CAENORHABDITIS elegans
- Publication
PLoS Genetics, 2024, Vol 20, Issue 5, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1011253