Enrico Schmidt et al. (2008) C.elegans Neuronal Development Meeting "The Parkinson's Disease Related Kinases LRK-1 and PINK-1 are Functionally Connected via Rho family GTPases in C.elegans"

Ursula Schaffer, Erika Gromoff, Natalja Tscherwinski, Ralf Baumeister, Enrico Schmidt, Julia Samann, Monika Messerschmid

[C.elegans Neuronal Development Meeting, 2008]

Parkinson''s Disease (PD) is characterized by the loss of projection neurons in the substantia nigra. Dominant mutations in alpha-synuclein and LRRK2 (leucine-rich-repeat kinase) and recessive mutations in Parkin, DJ-1 and PINK1 (PTEN-induced kinase) segregate with the familial variants of PD. Mutants in these genes have been linked to mitochondrial dysfunction and oxidative as well as ER stress vulnerability. However, a contribution of these mutants to the pathological processes, the first manifestations of which are cytoskeletal defects, is not known at present. Studies in mammalian support the idea that PINK1 forms a protein complex with DJ-1 and acts in the same pathway as Parkin. Furthermore, a biochemical interaction between LRRK2 and Parkin was suggested recently. Taking these multiple functional interactions into account, we reasoned that LRK-1 and PINK-1 could contribute to overlapping biological functions. In order to identify common targets for the kinases we created a protein interaction network of PD-related proteins based on genetic and biochemical approaches. Bioinformatical analyses of the interaction network suggested a possible connection of the PD-related kinases to members of the family of Rho GTPases and their targets and regulators, which are key players of the cytoskeletal regulation. Using combined pharmacological and genetic methods we were able to confirm the bioinformatical prediction. We show that both LRK-1 and PINK-1 affect axon guidance and cell migration in C. elegans via the small GTPases of the Rho family.