LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Caenorhabditis elegans Proteins*/metabolism ; Caenorhabditis elegans Proteins*/genetics ; Caenorhabditis elegans*/genetics ; Caenorhabditis elegans*/metabolism ; Synaptic Vesicles*/metabolism ; Synaptic Vesicles*/genetics ; Adaptor Protein Complex 3*/metabolism ; Adaptor Protein Complex 3*/genetics ; Lysosomes*/metabolism ; Lysosomes*/genetics ; Nerve Tissue Proteins*/metabolism ; Nerve Tissue Proteins*/genetics; Animals ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Protein Transport ; Protein Serine-Threonine Kinases/metabolism ; Protein Serine-Threonine Kinases/genetics ; Neurons/metabolism ; Kinesins/metabolism ; Kinesins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; Axons/metabolism ; Intercellular Signaling Peptides and Proteins

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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Update of: bioRxiv. 2023 Feb 26;:. (PMID: 36865111)

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P40 OD010440 United States OD NIH HHS; R01 GM135326 United States GM NIGMS NIH HHS

0 (Caenorhabditis elegans Proteins)
0 (Adaptor Protein Complex 3)
0 (Nerve Tissue Proteins)
0 (SYD-2 protein, C elegans)
EC 2.7.11.1 (LRK-1 protein, C elegans)
0 (UNC-104 protein, C elegans)
EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 3.6.4.4 (Kinesins)
0 (Intracellular Signaling Peptides and Proteins)
0 (Intercellular Signaling Peptides and Proteins)

Date Created: 20240509 Date Completed: 20240509 Latest Revision: 20240529

20240530

PMC11081264

10.1371/journal.pgen.1011253

38722918