Silencing synuclein at the synapse with PLK2.

The significance of α-synuclein (α-syn) phosphorylation to Parkinson disease (PD) pathology has been controversial since the initial identification of this posttranslational modification in intracellular Lewy bodies (1, 2). The modification of serine-129 (S129), which appears to be the most common phosphorylation site on α-syn (3, 4), has had the focus of attention. Although several different kinase families have been linked to modification of S129 in vitro, definitive in vivo evidence that a given kinase family causes the modification has been lacking (5). In addition to the lack of clarity regarding which kinases phosphorylate α-syn in a physiologically relevant context, it has been unclear whether phosphorylation of S129 is protective or harmful to neurons. The most significant problem in this regard has been that genetic manipulation of α-syn at S129—by mutation to either alanine or aspartate—has yielded varying results in cultured cells and different model organisms, including flies, worms, and rodents (5). Because the phosphorylation of S129 appeared to have no consistent effect on α-syn function in the cell, it has been unclear whether the process does anything more than reflect the magnitude of total α-syn levels in diseased neurons. In their article in PNAS, Oueslati et al. (6) now reveal a unique and unexpected effect coupled to S129 phosphorylation. In many studies of the phospho-specific epitopes of different proteins, it has turned out that knowing the identity of the kinase that phosphorylates a given protein in a physiological context can be just as important as knowing which specific residue is modified. Oueslati et al. (6) show that the phosphorylation of S129 of α-syn is no exception. This is because the kinase of interest, polo-like kinase 2 (PLK2), not only phosphorylates α-syn, but also escorts modified α-syn into the autophagy pathway for degradation. This dual kinase/chaperone activity (Fig. 1) provides key insight into the significance of α-syn phosphorylation, because in the absence of chaperone activity of PLK2, it is not clear that modification of α-syn at S129 has any major functional impact. The first evidence that α-syn could be phosphorylated at S129 by PLK family members came from a loss-of-function siRNA screen by Elan Pharmaceuticals, which identified both PLK2 and PLK3 as potential mediators of the modification (7). Importantly, this study also demonstrated that small-molecule inhibition and germ-line deletion of mouse Plk2 lead to decreased S129 phosphorylation in vivo. An ensuing study by Lashuel and colleagues confirmed the finding, and further demonstrated the specificity of PLK2 and PLK3 for α-syn compared with other synuclein isoforms (8). Two critical pieces of information in the PLK2/α-syn connection were missing, however: namely, an understanding of the functional consequences of the interaction and how it affects α-syn pathology. In addition to its kinase domain, PLK2 also contains a namesake polo-box domain, which functions as a phospho-ser/thr binding motif (9). Oueslati et al. (6) demonstrate that after phosphorylating α-syn at S129, PLK2 binds α-syn via this polo-box domain and escorts it into a degradation pathway, most likely of autophagy/lysosomal origin (Fig. 1). The precise identity of which autophagic pathway is involved is unclear (macroautophagy vs. chaperone-mediated autophagy), but PLK2-mediated α-syn degradation is blocked by both early and late inhibitors of autophagy and does not appear to involve proteosomal activity. Most importantly, this study by Oueslati et al. (6) also shows that both PLK2 kinase activity and an intact S129 site are required for degradation of excess α-syn in the rat brain. Thus, less α-syn protein accumulated and fewer neurons died when rat brain polo-box kinase -OH S129