LRRK2: a problem lurking in vesicle trafficking?

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Piccoli et al. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the major genetic cause of Parkinson's disease (PD), accounting for ϳ5% of familial and 0.5–2% of sporadic cases (Dächsel and Farrer, 2010). Although the strong association between LRRK2 and PD has led to extensive research over the last several years, LRRK2 function in health and disease remains unclear. A recent study by Piccoli et al. (2011) investigated the role of LRRK2 in the control of vesicle dynamics by analyzing mouse primary cortical neuron syn-apses. The authors showed that silencing LRRK2 in presynaptic neurons altered their ability of to orchestrate excitatory synaptic transmission. EPSCs evoked in wild-type postsynaptic neurons by depolarization of presynaptic neurons in which LRRK2 was silenced were twice as large as those evoked by depolariza-tion of unsilenced control neurons [Piccoli et al. (2011), their Fig. 2]. This suggested that LRRK2 is involved in the control of vesicle dynamics in presynaptic neurons, which is consistent with data from Alegre-Abarrategui et al. (2009), who demonstrated by immunoelectron microscopy that LRRK2 localizes to transmembrane lipid domains, as well as vesicular structures. Piccoli et al. (2011) used immuno-staining against the synaptic vesicle protein synaptotagmin to determine that LRRK2-silenced neurons have unusually high numbers of active synapses under resting conditions. Moreover, when cells were depolarized with KCl, which increases vesicle release, no additional increase in synaptotagmin staining was found in these cells [Piccoli et al. (2011), their Fig. 3]. Furthermore, a pulse of hy-pertonic sucrose, which triggers exocyto-sis of the entire readily releasable pool of synaptic vesicles (Rosenmund and Ste-vens, 1996), had no apparent effect in LRRK2-silenced neurons, suggesting that these cells mobilized the maximum number of readily releasable vesicles under resting conditions [Piccoli et al. (2011), their Fig. 8]. Although electrophysiology and im-munostaining experiments suggested that more synaptic vesicles were released by LRRK2-silenced neurons, EM analysis showed fewer vesicles in physical contact with the presynaptic membrane [Piccoli et al. (2011), their Fig. 7]. This discrepancy can be explained because the number of docked vesicles does not directly correspond to the readily releasable pool. Additionally this can be justified by …