Chaperone complex BAG2–HSC70 regulates localization of Caenorhabditis elegans leucine‐rich repeat kinase LRK‐1 to the Golgi

Abstract

Mutations in LRRK2 are linked to autosomal dominant forms of Parkinson's disease. We identified two human proteins that bind to LRRK2: BAG2 and HSC70, which are known to form a chaperone complex. We characterized the role of their Caenorhabditis elegans homologues, UNC-23 and HSP-1, in the regulation of LRK-1, the sole homologue of human LRRK2. In C. elegans, LRK-1 determines the polarized sorting of synaptic vesicle (SV) proteins to the axons by excluding SV proteins from the dendrite-specific transport machinery in the Golgi. In unc-23 mutants, SV proteins are localized to both presynaptic and dendritic endings in neurons, a phenotype also observed in lrk-1 deletion mutants. Furthermore, we isolated mutations in the hsp-1 gene that can suppress the unc-23, but not the lrk-1 defect. We show that UNC-23 determines LRK-1 localization to the Golgi apparatus in cooperation with HSP-1. These results describe a chaperone-dependent mechanism through which LRK-1 localization is regulated.

LRRK2 at the interface of autophagosomes, endosomes and lysosomes

“…In the latter case, we have found that Rab7L1/Rab29 is important for recruiting LRRK2 to the TGN, along with the clathrin-uncoating protein cyclin-G associated kinase (GAK) and the co-chaperone BAG5. This protein complex may be conserved as similar proteins are important for the recruitment of Lrk-1 to the golgi apparatus in C elegans [74], Importantly, Rab7L1 and GAK are nominated to be risk factors for sporadic PD [14]. Clearance of Golgi-derived vesicles by the LRRK2 complex including Rab7L1 is enhanced by mutations across all enzymatic domains of LRRK2 whereas hypothesis testing LRRK2 mutations, including those that are kinase dead or cannot bind GDP/GTP, were ineffective in TGN vesicle clearance [73].…”

Homeostatic Roles of the Proteostasis Network in Dendrites

“…Hsc70, a non-heat-inducible form of Hsp70 may also be necessary for neurite differentiation. Mutations in the BAG2-Hsc70 chaperone complex was found to cause synaptic vesicles, normally located in the axon, to appear in the spines and processes of dendrites (Fukuzono et al, 2016). Chaperones contribute a great deal to cytoskeletal stability, which is especially important for neurons to sustain their complex processes ( Table 2; Bakthisaran et al, 2015;Nefedova et al, 2015;Nefedova et al, 2017;Kelliher et al, 2019;Muranova et al, 2019;Vallin and Grantham, 2019;Muranova et al, 2020).…”

“…Chaperones contribute a great deal to cytoskeletal stability, which is especially important for neurons to sustain their complex processes ( Table 2; Bakthisaran et al, 2015;Nefedova et al, 2015;Nefedova et al, 2017;Kelliher et al, 2019;Muranova et al, 2019;Vallin and Grantham, 2019;Muranova et al, 2020). Many chaperones are implicated specifically in axonal morphology: manipulation of several small heat shock proteins as well as Hsp70 and 90 was found to significantly decrease synapse number in Drosophila neuromuscular junctions (Santana et al, 2020), and an Hsp70 orthologue has been found to assist in polarized trafficking of synaptic vesicle proteins to axons (Fukuzono et al, 2016).…”

“…However, since these studies were performed in younger and older mice, respectively, the findings together could indicate age-dependent dendritic effects of α-synuclein expression, perhaps underlying some of the symptoms of PD. Hsc70, Hsp27 and the mitochondrial chaperone, TRAP1, are also implicated in different hereditary forms of PD (Fukuzono et al, 2016;Brunelli et al, 2020;Vicente Miranda et al, 2020).…”

“…Hsp70 is known to mediate disassembly of protein aggregates in this manner (Fukuzono et al, 2016;Ciechanover and Kwon, 2017). Chaperones not only can correct misfolded proteins but can disassemble aggregations and initiate UPS and autophagic pathways (Mymrikov et al, 2011;Fukuzono et al, 2016;Kasza et al, 2016;Pavel et al, 2016;Ciechanover and Kwon, 2017;Chaari, 2019). While they may or may not participate in physically transporting misfolded proteins to lysosomes, other chaperones -including CCT, Hspb6, and Hspb8 -are implicated in positively regulating autophagy (Mymrikov et al, 2011;Pavel et al, 2016).…”