Silencing synuclein at the synapse with PLK2

Abstract

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). Oues...

Development and characterization of polo-like kinase 2 loaded nanoparticles-A novel strategy for (serine-129) phosphorylation of alpha-synuclein

“…Notably, controversial publications have generated considerable debate, suggesting that PLK2 may have a putative toxic or protective attribute, which is probably due to the complex interplay of factors that occur in dopamine neurons. In this sense, Oueslati et al (2013) demonstrated that PLK2 enhances α-syn clearance and suppresses its toxicity in vivo while Looyenga and Brundin (2013) suggested that prolonged periods of PLK2 activity may be detrimental to neurons. There is thus a lack of consensus concerning whether α-syn phosphorylation could lead to neuronal toxicity and LB aggregation.…”

Polo-like kinase 2 activates an antioxidant pathway to promote the survival of cells with mitochondrial dysfunction

“…The synaptic protein SPAR is a PLK2 substrate involved in the regulation of neuronal plasticity [11]. In addition, PLK2 can phosphorylate and promote selective autophagic clearance of α-synuclein, a synaptic protein that accumulates in the Lewy bodies of Parkinson’s disease, a neurodegenerative condition associated with mitochondrial dysfunction and oxidative stress [12–16]. These different functions of PLK2 in proliferating and post-mitotic cells suggest that the phosphorylation of different substrates represents cell type-specific adaptive processes activated under conditions of stress and is also consistent with the initial identification of PLK2 as an immediate early response gene [17].…”

Identification of the PLK2-Dependent Phosphopeptidome by Quantitative Proteomics

“…α-Synuclein is constitutively phosphorylated at low levels in normal brain and an accumulation of α-synuclein pS129 in Lewy bodies is observed in Parkinson disease and other synucleinopathies. Although the pathophysiology of the Ser-129 phosphorylation in Parkinson's disease is not completely understood and it has not been clarified whether this phosphorylation is protective or harmful for neurons, PLK2 is considered a very promising target for Parkinson disease treatment [15] , [16] , [17] .…”