Mutations in two genes encoding the putative kinases LRRK2 and PINK1 have been associated with inherited variants of Parkinson disease. The physiological role of both proteins is not known at present, but studies in model organisms have linked their mutants to distinct aspects of mitochondrial dysfunction, increased vulnerability to oxidative and endoplasmic reticulum stress, and intracellular protein sorting. Here, we show that a mutation in the Caenorhabditits elegans homologue of the PTEN-induced kinase pink-1 gene resulted in reduced mitochondrial cristae length and increased paraquat sensitivity of the nematode. Moreover, the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons. We demonstrate that in the absence of lrk-1, the C. elegans homologue of human LRRK2, all phenotypic aspects of pink-1 loss-offunction mutants were suppressed. Conversely, the hypersensitivity of lrk-1 mutant animals to the endoplasmic reticulum stressor tunicamycin was reduced in a pink-1 mutant background. These results provide the first evidence of an antagonistic role of PINK-1 and LRK-1. Due to the similarity of the C. elegans proteins to human LRRK2 and PINK1, we suggest a common role of both factors in cellular functions including stress response and regulation of neurite outgrowth. This study might help to link pink-1/PINK1 and lrk-1/LRRK2 function to the pathological processes resulting from Parkinson disease-related mutants in both genes, the first manifestations of which are cytoskeletal defects in affected neurons. Mutations in the Parkinson disease (PD)2 -related gene PINK1 have been associated with increased sensitivity to oxidative stress and mitochondrial dysfunction (1-4). Although a series of reports support a localization of PINK1 only in mitochondria (5-7), recent studies have shown that a portion of endogenous PINK1 is also distributed to the cytoplasm (8 -11). Notably, the cytoplasmic kinase activity and not the mitochondrial targeting of PINK1 seems to be prerequisite of its protective effects against mitochondrial stress (12).The GTPase-regulated kinase LRRK2, another gene associated with familial PD, has been linked to the biogenesis and regulation of vesicular transport (13,14). In support of this notion, the C. elegans lrk-1, the LRRK2 homologue, has recently been shown to be involved in synaptobrevin-associated vesicular transport (15). Moreover, the Dictyostelium homologue of LRRK2/LRK-1 proteins, GbpC, a cGMP-binding protein is required for the normal phosphorylation and cytoskeletal assembly of myosin (16). Based on this data, it had been anticipated that PINK1/PINK-1 and LRRK2/LRK-1 might be involved in distinct cellular functions, whereas pathological mutations in both genes, leading either to loss-of-function (PINK1) or gain-of-function (LRRK2), result in a similar phenotype, the loss of dopaminergic neurons.In the present study, we found a functional connection between their Caenorhabditits elegans homologues pink-1 and lrk-1. We demonstrate that loss of C. elega...

Apoptotic cell death is an integral part of cell turnover in many tissues, and proper corpse clearance is vital to maintaining tissue homeostasis in all multicellular organisms. Even in tissues with high cellular turnover, apoptotic cells are rarely seen because of efficient clearance mechanisms in healthy individuals. In Caenorhabditis elegans, two parallel and partly redundant conserved pathways act in cell corpse engulfment. The pathway for cytoskeletal rearrangement requires the small GTPase CED-10 Rac1 acting for an efficient surround of the dead cell. The CED-10 Rac pathway is also required for the proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. Parkin, the mammalian homolog of the C. elegans PDR-1, interacts with Rac1 in aged human brain and it is also implicated with actin dynamics and cytoskeletal rearrangements in Parkinsons's disease, suggesting that it might act on engulfment. Our genetic and biochemical studies indicate that PDR-1 inhibits apoptotic cell engulfment and DTC migration by ubiquitylating CED-10 for degradation.