. Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J Biol Chem. 2011 May 6;286(18):16140-9. PubMed.

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  1. This paper by Chan et al. develops the previous reports of an effect of LRRK2 on neurite length to include a specific molecular effector, Rac1. That LRRK2 influences neurite length in cell culture is reasonably well established, as several labs have replicated the original findings of MacLeod et al. (1) showing that overexpressed LRRK2, particularly mutant forms, decreases neurite length while knockout of the endogenous LRRK2 gene is associated with increased neurite length (2,3), although that latter point is contradicted here (see below). If, as Chan et al. suggest, Rac1 is an important effector of LRRK2, then this may provide additional important molecular information on the effects of LRRK2. Importantly, the effects seem to be mediated by relocalization of a Rac1-LRRK2 complex to the plasma membrane. It is known that a proportion of LRRK2 is associated with membranes (e.g., 4), and so the implication here is that activated LRRK2 is particularly enriched in these membrane compartments. It would be relatively straightforward to examine LRRK2 and Rac1 activity in membrane fractions compared to bulk LRRK2, and to test the idea that Rac1, particularly constitutively active Rac1, can activate LRRK2. The identification of ways to activate LRRK2 is something the field has been missing, and this is important.

    Another crucial point made by Chan et al. is that mutations in LRRK2 all affect Rac1 binding or function. As the authors say, this is important because parsimony suggests that the most likely pathogenic effect of mutant LRRK2 will be shared by all mutations, a point made elsewhere (5). One small issue is that there isn’t yet much evidence that LRRK2 influences neurite length in the mature adult nervous system, but perhaps this is because we still need to identify the in vivo activators of LRRK2. Again, Rac1 becomes a reasonable candidate for this process. It is also probably important to understand how endogenous wild-type LRRK2 acts, and here the picture remains confused. The present paper says that siRNA to LRRK2 decreases neurite length in human neuroblastoma cells (Figure 7 of Chan et al.), but previous studies actually showed a small but significant increase in neurite length with LRRK2 genomic knockouts of the murine gene (2,3). It is important to determine why these results differ, as it is critical to understanding how mutations work functionally compared to the normal alleles—the work of Chan et al. suggests a dominant-negative effect, whereas previous results would not be compatible with this suggestion. Why these results differ is not clear; there could be compensation in the knockouts that overshoots, or it could be that the siRNA approach has some small off-target effect.

    Overall, this is an important paper that should be able to be replicated by several labs working in the area.

    References:

    . The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron. 2006 Nov 22;52(4):587-93. PubMed.

    . Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J Neurosci. 2009 Nov 4;29(44):13971-80. PubMed.

    . A comparative study of Lrrk2 function in primary neuronal cultures. Parkinsonism Relat Disord. 2010 Dec;16(10):650-5. PubMed.

    . Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry. 2010 Jul 6;49(26):5511-23. PubMed.

    . The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci. 2010 Dec;11(12) Epub 2010 Nov 19 PubMed.

  2. LRRK2 mutations lead to typical Parkinson’s disease and represent a very common cause of both familial and sporadic PD. A variety of studies have been devoted to characterize the pathophysiological functions of LRRK2 and its mutations in order to understand the cellular and molecular mechanisms of PD. Over the past five years, accumulating evidence indicates an important function of LRRK2 in regulating the dynamics of actin and microtubule assembly during neuron development and degeneration (1). Towards this direction, Chan and colleagues, in this recent Journal of Biological Chemistry paper, described a strong physical and functional interaction between LRRK2 and Rac1. Rac1 belongs to a family of small GTPases critical for many cellular functions, including dynamic regulation of the actin network during cell migration. It appears that LRRK2 regulates the activity and subcellular location of Rac1; while overexpression of Rac1 abrogates the PD-related G2019S LRRK2-induced neurite shortening defect. However, it is intriguing to find out that different PD-related LRRK2 mutations exert rather diverse effects on the function of Rac1. It is also unclear whether the assembly and subcellular location of actin is affected in these cells. In addition, the present studies were mainly carried out in cell lines. It is important to evaluate the consequence of LRRK2 and Rac1 interaction in a more physiological context. Nonetheless, this study provides new insight into the molecular pathways that link LRRK2 with actin and cytoskeleton dynamics.

    References:

    . LRRK2 function on actin and microtubule dynamics in Parkinson disease. Commun Integr Biol. 2010 Sep;3(5):396-400. PubMed.