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 …