Edited by Roger J. ColbranIncreasing lines of evidence support the causal link between ␣-synuclein (␣-syn) accumulation in the brain and Parkinson's disease (PD) pathogenesis. Therefore, lowering ␣-syn protein levels may represent a viable therapeutic strategy for the treatment of PD and related disorders. We recently described a novel selective ␣-syn degradation pathway, catalyzed by the activity of the Polo-like kinase 2 (PLK2), capable of reducing ␣-syn protein expression and suppressing its toxicity in vivo. However, the exact molecular mechanisms underlying this degradation route remain elusive. In the present study we report that among PLK family members, PLK3 is also able to catalyze ␣-syn phosphorylation and degradation in living cells. Using pharmacological and genetic approaches, we confirmed the implication of the macroautophagy on PLK2-mediated ␣-syn turnover, and our observations suggest a concomitant co-degradation of these two proteins. Moreover, we showed that the N-terminal region of ␣-syn is important for PLK2-mediated ␣-syn phosphorylation and degradation and is implicated in the physical interaction between the two proteins. We also demonstrated that PLK2 polyubiquitination is important for PLK2⅐␣-syn protein complex degradation, and we hypothesize that this post-translational modification may act as a signal for the selective recognition by the macroautophagy machinery. Finally, we observed that the PD-linked mutation E46K enhances PLK2-mediated ␣-syn degradation, suggesting that this mutated form is a bona fide substrate of this degradation pathway. In conclusion, our study provides a detailed description of the new degradation route of ␣-syn and offers new opportunities for the development of therapeutic strategies aiming to reduce ␣-syn protein accumulation and toxicity. Parkinson's disease (PD)2 is a neurodegenerative disorder characterized by the progressive loss of vulnerable neuronal populations in the brain and the accumulation of proteinaceous intraneuronal inclusions called Lewy bodies (1, 2). These inclusions mainly consist of a presynaptic protein, ␣-synuclein (␣-syn) (3-5). Converging lines of evidence from neuropathological studies and experimental models support the central role of ␣-syn aggregation and toxicity in the pathogenesis of PD (3, 6). This ␣-syn abnormal accumulation is in part triggered by its gene duplications/triplications or by the impairment of its degradation (3, 6). Therefore, enhancing ␣-syn elimination may represent a viable therapeutic strategy for the treatment of PD and related disorders.However, the question on how ␣-syn is eliminated in vivo has yielded controversial results (7). Although some studies reported specific elimination of the monomeric and fibrillar ␣-syn forms by the ubiquitin-proteasome system (8 -10), others reported the degradation of this protein via the autophagy-lysosomal pathway, notably the chaperone-mediated autophagy (10 -12). This controversy and the lack of known selective routes for ␣-syn elimination precluded the development ...

Neurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of α-synuclein (α-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of α-syn aggregation in PD.

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