Interacting with LRRK2

Mutations in leucine-rich repeat kinase 2 (LRRK2) has not only been accounted for significant percentage of familial Parkinson’s disease (PD) but also 5% of sporadic cases. LRRK2 is a high molecular protein consisting of multiple conserved domains, including two enzymatic domains and several protein-protein interaction domains. Endogenous low expression of LRRK2 and lacking of effective antibodies against it make biochemical analysis challenging. Because of limited tools, it also causes most studies on LRRK2 stay at in vitro level. However it is still important to gain precious knowledge of LRRK2 with in vitro biochemical investigations.  

Hsu and her colleagues have published their finding that LRRK2 interacts with MKK6 in mammalian cells by overexpressing tagged LRRK2 and MKK6. According to the studies, they have provided evidence consistent with the recent studies, at least partially, by Gloeckner et al, who use purified recombinant protein from prokaryotic system. The authors also have found that expression of MKK6 has increased in the presence of LRRK2 and vice versa. It is more intriguing that overexpression of these two proteins has changed the subcellular localization of MKK6.  The mechanisms of increase at protein level and the physiological meaning of the change of subcellular localization still need to be further investigated. Furthermore, authors have used C. elegan to examine possible physiological function of the interaction between LRRK2 and MKK6. The result is interesting but need to be interpreted carefully. According to the study by Ignacio Marin at Journal of Molecular Evolution, the LRRK2 and LRRK genes in C. elegans are not real orthologues but rather paralogues.  (Orthologues are genes in different species that evolved from a common ancestral gene by speciation. Normally, orthologues retain the same function in the course of evolution. Paralogues are genes related by duplication within a genome. Orthologues retain the same function in the course of evolution, whereas paralogues evolve new functions, even if these are related to the original one.)

In general, the study by Hsu and her colleagues has carefully characterized the biochemical interaction between LRRK2 and MKK6 and offered valuable information of LRRK2 might be related to the stress response.