Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo

An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related syn...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (41), p.E3945-E3945
Hauptverfasser: Oueslati, Abid, Schneider, Bernard L, Aebischer, Patrick, Lashuel, Hilal A
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container_title Proceedings of the National Academy of Sciences - PNAS
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creator Oueslati, Abid
Schneider, Bernard L
Aebischer, Patrick
Lashuel, Hilal A
description An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances α-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of α-synuclein requires both phosphorylation at S129 and PLK2/ α-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human α-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by α-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and α-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies. [PUBLICATION ABSTRACT]
doi_str_mv 10.1073/pnas.1309991110
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subjects Kinases
Parkinson's disease
Phosphorylation
Poliomyelitis
Proteins
Rodents
Toxicity
title Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo
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