MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A.
The familial Parkinsonism gene LRRK2 regulates neurite process morphology.
Neuron. 2006 Nov 22;52(4):587-93.
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This paper shows in a striking way that the Lrrk2 gene, which is associated with dominantly inherited PD in humans, has dramatic effects on neuronal morphology in vitro and in vivo. A key point from this study is that the kinase activity is critical for many of these effects. This is shown by the increased activity of hyperactive kinase variants (especially G2019S, in the kinase domain) and by the lack of effect of a kinase-dead version. This has important implications for how we design therapies for LRRK2-related PD, as one can imagine kinase inhibitors being potential drugs for this disease. I should point out my own bias here, as we have shown that cell death in similar models is ameliorated by genetically inactivating the kinase (Greggio et al., 2006). The results of MacLeod et al. suggest a strong correlation between the kinase activity of LRRK2 and neuritic morphology.
As ever, there are a few remaining questions about how the kinase activity contributes to pathogenic effects of LRRK2 and, importantly for reading MacLeod et al., which effects should be considered pathogenic. To take the second question, it is interesting that some mutations (G2019S, I2020T) affect neurite length, whilst others (R1441C, Y1699C) have marginal effects. We have to assess the pathogenicity of mutations from the human genetic data rather than surrogate measures of activity in experimental systems. Both Y1699C and R1441C show clear segregation in multiple families and pass the test of pathogenicity. Therefore, we are forced to conclude that the effects on neurite outgrowth are not a reflection of whether the mutations are pathogenic, and that this assay fails to capture all possible mechanisms by which LRRK2 causes disease.
The above discussion is not meant to say that the effects of LRRK2 on neurite outgrowth are not interesting, but that these developmental effects may be distinct from the neurodegenerative effects. This is perhaps not that surprising as many kinases have multiple substrates, which can be involved in many different cellular processes. The concept is that LRRK2 phosphorylates one or more substrates that play a critical role in the generation of neuronal morphology. Also, LRRK2 may be a kinase for substrates that trigger cell loss and Lewy body formation in the adult brain. Without knowing the substrates, one cannot conclude whether these processes are related. This illustrates the next key question for LRRK2 research: what are the substrates? Knowing that information will allow us to move a little further down the road in identifying how this kinase plays roles in normal CNS function as well as disease.
Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR.
Kinase activity is required for the toxic effects of mutant LRRK2/dardarin.
Neurobiol Dis. 2006 Aug;23(2):329-41.