. LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3ß. J Neurosci. 2010 Sep 29;30(39):13138-49. PubMed.


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  1. This study by Lin et al. provides an excellent opportunity to reevaluate the proposed role of LRRK2 on neurite outgrowth and maintenance. Work from the Abeliovich lab first showed that LRRK2, and especially mutant LRRK2, can limit the outgrowth of neurites in culture, but it has remained unclear whether this occurs in vivo. Using Drosophila models in the way that Lin et al. have done allowed the authors to test the effects of multiple different LRRK2 variants and to establish some of the mechanisms involved.

    One of the most interesting results here is that the effects of G2019S mutant LRRK2 on neurites in vivo involves tau. Some authorities (Hardy and Orr, 2006) have advocated for several years that tau is a likely player in parkinsonism, and recent results in genomewide association studies have confirmed a genetic role, at least in some populations (Simon-Sanchez et al., 2009; Hamza et al., 2010). Lin et al. begin to provide a mechanistic explanation, namely that LRRK2 binds to GSK3β to promote tau phosphorylation at threonine 212/serine 214. This is an eminently testable hypothesis in other systems where LRRK2 and GSK3β are expressed (such as in human or mouse brain). This does need to be tested further, because if the effects are restricted to tau T212/S214, then there may be some specificity that makes tau in Parkinson’s different from tau in Alzheimer’s, where many more sites are phosphorylated.

    One area of difficulty is with the idea that there are two mechanisms at work in this model. To their credit, the authors are very clear on this issue and say that while G2019S and other LRRK2 variants (including wild-type, a kinase dead version, and a second pathogenic mutant) all cause dendritic arborization defects, tau only accumulates with the G2019S mutant. One simple, if potentially unpopular, interpretation is that the tau-independent mechanism is due to increased kinase activity of LRRK2, but that the tau phosphorylation mechanism is related more to overexpression itself. Therefore, G2019S LRRK2 causes degeneration through dysregulated kinase activity, and introducing the kinase inactivating mutation K1906M can block this, as the researchers show. The next important point, and here the authors slightly misquote the literature, is that R1441C does not cause increased kinase activity to the same extent as G2019S (reviewed in Greggio and Cookson, 2009). Therefore, R1441C having the same effect as wild-type LRRK2 is probably best interpreted as the dendritic effects being a simple consequence of basal kinase activity. R1441C is pathogenic in familial cases, so this assay does not capture all aspects of the mechanisms that may be present in human LRRK2 disease. Whether there are circumstances where mutations outside of the kinase domain can acquire enhanced activity still needs to be answered.

    I say this is potentially unpopular as an idea because, if true, this means that we have to be very cautious with interpretation of overexpression studies. Not to say that we shouldn’t do them—my lab uses overexpression most days—more that the correct controls need to be very carefully selected. LRRK2 is a large protein that is usually expressed at low levels in most cells that we have looked at, and is not therefore likely to be constrained evolutionarily to have ideal protein behavior at higher expression levels. Furthermore, the Drosophila LRK protein and human LRRK2 are different in several respects, including size and key residues in the activation loop of the kinase domain. In these types of experiments, expression is of a foreign protein that may or may not be correctly regulated. Probably the best controls will be other similar large molecules that can be manipulated in the same way as LRRK2 but are not associated with human PD—LRRK1 is one we’ve previously considered (Greggio et al., 2007).

    Overall, Lin et al. have demonstrated how combined genetic and biochemical approaches can be powerful in identifying in vivo mechanisms leading to neurodegeneration. That tau is a candidate here is perhaps the most exciting news, and certainly should push the Parkinson’s field to consider that, if there are tactics that are being developed for other diseases that are more traditionally considered tauopathies, that can be applied to this disorder.


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