LRK-1, a C. elegans PARK8-Related Kinase, Regulates Axonal-Dendritic Polarity of SV Proteins

Abstract

Neurons are polarized cells that contain distinct sets of proteins in their axons and dendrites. Synaptic vesicles (SV) and many SV proteins are exclusively localized in the presynaptic regions but not in dendrites. Despite their fundamental importance, the mechanisms underlying the polarized localization of SV proteins remain unclear. The transparent nematode Caenorhabditis elegans can be used to examine sorting and transport of SV proteins in vivo. Here, we identify a novel protein kinase LRK-1, a C. elegans homolog of the familial Parkinsonism gene PARK8/LRRK2 that is required for polarized localization of SV proteins. In lrk-1 deletion mutants, SV proteins are localized to both presynaptic and dendritic endings in neurons. This aberrant localization of SV proteins in the dendrites is dependent on the AP-1 mu1 clathrin adaptor UNC-101, which is involved in polarized dendritic transport, but not on UNC-104 kinesin, which is required for the transport of SV to presynaptic regions. The LRK-1 proteins are localized in the Golgi apparatus. These results suggest that the LRK-1 protein kinase determines polarized sorting of SV proteins to the axons by excluding SV proteins from the dendrite-specific transport machinery in the Golgi.

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

“…http://bmbreports.org Efforts to generate LRRK2 transgenic or deletion mutant animals were also attempted in flies and worms, two very useful experimental animals for this purpose. Abnormal localization of SNB-1, an orthologue of mammalian synaptobrevin2/VAMP2, in both presynaptic and dendritic ends has been reported in the deletion mutant of LRK-1, an orthologue of LRRK2 in C. elegans (22). This result suggested that LRRK2 may be involved in regulation of specific vesicle/cargo transport to proper neurites.…”

“…The kinase domain of LRRK2 was reported to share homology with mixed-lineage kinase (MLK; 18) and receptor interacting protein kinase (RIPK; 20). Although both LRRK1 and LRRK2 are present in mammals such as human, rat and mouse, only one orthologue of LRRK was identified in Drosophila and C. elegans, respectively called dLRRK and LRK-1 (21,22).…”

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…In C. elegans, LRK-1 plays a pivotal role in polarized sorting of synaptic vesicle proteins to the Golgi [147]. A LRRK2 interactor, ArfGAP1, associates with the Golgi apparatus as a part of the coat protein I complex [148,149].…”

Update on the Functional Biology of Lrrk2

“…In the nematode worm Caenorhabditis elegans, knockout of the paralog LRK-1 suggests a role in polarized sorting of synaptic vesicle proteins to axons by excluding them from dendritespecific transport machinery in the Golgi [73]. LRK-1-knockout worms have a chemosensory deficit, which is interesting since marked olfactory dysfunction is a frequent and early abnormality in PD.…”