Authentically Phosphorylated α-Synuclein at Ser129 Accelerates Neurodegeneration in a Rat Model of Familial Parkinson's Disease

Sato, Hiroyasu; Arawaka, Shigeki; Hara, Shotaro; Fukushima, Satoshi; Koga, Kaori; Koyama, Shingo; Kato, Takeshi

doi:10.1523/jneurosci.3967-11.2011

Cited by 118 publications

(111 citation statements)

References 44 publications

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“…However, the relevance of αS phosphorylation at S129 for neurotoxicity and disease remains controversial (Basso et al, 2013). While some reports report a beneficial effect (Kuwahara et al, 2012;Oueslati et al, 2013), others identified deleterious consequences (Chen and Feany, 2005;Sato et al, 2011). A separate study found no effects of this posttranslational modification (McFarland et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 -the Drosophila ortholog of Rab8a -ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.

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Section: Discussionmentioning

confidence: 99%

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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“…In transgenic Drosophila, the coexpression of α-syn with GRK2 enhances α-syn phosphorylation at S129 and accelerates neuronal loss compared with nonphosphorylated α-syn (45). Recently, Sato et al reported that GRK6 overexpression moderately accelerates A53T α-syn toxicity in an AAV-based rat model of PD, in an α-syn phosphorylation-dependent manner (46). Therefore, clear discrepancies are found between different kinases with respect to their effect on α-syn toxicity in vivo.…”

Section: Plk2 Activity Enhances α-Syn Autophagic Clearance In Cell Cumentioning

confidence: 99%

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

Oueslati¹,

Schneider

Aebischer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

170

201

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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.adeno-associated virus | animal model | serum inducible kinase P arkinson disease (PD) is a neurodegenerative disorder characterized by the progressive neuronal loss in different brain regions, including the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) (1, 2). Pathologically, PD is characterized by the presence, in surviving DA neurons, of intracellular inclusions called Lewy Bodies (LBs) and Lewy Neurites (LNs) (3). These fibrillar aggregates are mainly composed of the presynaptic protein α-synuclein (α-syn) (4). Converging evidence from pathologic, genetic, biochemical, and biophysical studies supports the hypothesis that α-syn accumulation and misfolding play a central role in the pathogenesis of PD and related disorders, which are altogether referred to as synucleinopathies (5).Although α-syn is constitutively phosphorylated at low levels (<4%) at S129 (pS129) in normal brains (6-8), a clear accumulation of pS129 (>90%) is found in LBs (8, 9) and in the brain of animal models of synucleinopathies (7,(10)(11)(12). The roles of this major posttranslational modification in regulating α-syn physiology and LB formation and/or neurodegeneration in PD remain elusive.Recently, our group and others (13-15) demonstrated that Pololike kinase 2 (PLK2), a serine/threonine kinase playing a central role in cell division, oncogenesis, and synaptic regulation in the adult brain (16-19), efficiently phosphorylates α-syn, with an exclusive preference for the S129 site. Unlike other kinases that were reported to partially phosphorylate α-syn at S129, PLK2 phosphorylates α-syn with quantitative conversion in vitro (>95%) and in mammalian cell lines (13-15).Interestingly, PLK2 expression levels are significantly up-regulated in the midbrain of aged monkeys and correlate with increased pS129 levels in dopaminer...

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“…Perhaps modulating the activity of the G protein-coupled receptor kinase (GRK) 2, another kinase known to phosphorylate α-synuclein at Ser129 [188,191,210], or AMP kinase, whose overexpression increases aggregation and causes decreased neurite outgrowth in primary neuronal cultures [211], may be beneficial. Interestingly, α-synuclein phosphorylation [212] and pathogenicity may be mediated, at least in part, by LRRK2 [213], a kinase that when mutated causes inherited forms of PD and which is the target of extensive drug discovery efforts.…”

Section: Phosphorylationmentioning

confidence: 99%

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

Esposito

2014

Topics in Medicinal Chemistry

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α-Synuclein is a dynamic protein capable of assuming an ensemble of physiological and pathological structures. Its primary role in Parkinson's disease (PD) pathogenesis makes it an attractive though nonconventional therapeutic target. An understanding of α-synuclein intra-and intermolecular interactions and posttranslational modifications that lead to its misfolding, aggregation, accumulation, and cell-to-cell prion-like spreading is necessary to inform the design of α-synuclein-directed therapeutics. Native α-synuclein interacts with membranes and plays an important role in synaptic transmission and vesicle trafficking at the presynaptic terminal, though aggregated α-synuclein may be compromised in its ability to perform these functions. In addition to discussing α-synuclein structural biology, this chapter explores the variety of experimental therapeutic approaches currently under investigation that aim to maintain physiological α-synuclein levels, limit toxic aggregates, and lessen effects of misfolded α-synuclein on cellular homeostasis. For example, oligonucleotide-based approaches limit α-synuclein gene expression. In addition, select small molecules and peptides inhibit α-synuclein aggregation at substoichiometric concentrations in favor of less structured, more soluble, and less toxic oligomers that may be better substrates for clearance. Some small molecules also remodel existing α-synuclein fibrils. Modest chemical changes to these small molecules can greatly impact their mechanism of action. Finally, α-synuclein-directed immunotherapy enhances the lysosomal clearance of α-synuclein in experimental models and is currently in clinical trials. Other therapeutic approaches target α-synuclein posttranslational modifications, aim to limit its impact on mitochondria or its ability to alter gene expression in the nucleus.

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Authentically Phosphorylated α-Synuclein at Ser129 Accelerates Neurodegeneration in a Rat Model of Familial Parkinson's Disease

Cited by 118 publications

References 44 publications

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

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

Targeting α-Synuclein as a Parkinson’s Disease Therapeutic

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