Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model

Khandelwal, Preeti J.; Dumanis, Sonya B.; Feng, Linyin; Maguire‐Zeiss, Kathleen A.; Rebeck, G. William; Lashuel, Hilal A.; Moussa, Charbel

doi:10.1186/1750-1326-5-47

Cited by 75 publications

(84 citation statements)

References 50 publications

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“…Another protective role of Parkin against α-synuclein toxicity in PD would be the reduction in the Parkin-induced phosphorylation state of α-synuclein, which would reduce α-synuclein aggregation (Khandelwal et al, 2010). Mutations in LRRK2…”

Section: Linking Oxidative Stress and Mitochondrial Dynamics In Pd Amentioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

144

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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Section: Linking Oxidative Stress and Mitochondrial Dynamics In Pd Amentioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

144

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“…Although the effect of phosphorylation at S129 has been investigated in rat (Gorbatyuk et al, 2008;Azeredo da Silveira et al, 2009;McFarland et al, 2009) and fly models of PD (Chen and Feany, 2005), the role of S87 phosphorylation in ␣-syn fibrillogenesis, LB formation and neurotoxicity in vivo remains unexplored. A recent study by Khandelwal et al (2010) demonstrated that overexpression of parkin protects against ␣-syn-induced toxicity by reducing the levels of both pS87 and pS129 in vivo, suggesting that phosphorylation at these residues is a pathological event.…”

Section: Introductionmentioning

confidence: 99%

Mimicking Phosphorylation at Serine 87 Inhibits the Aggregation of Human α-Synuclein and Protects against Its Toxicity in a Rat Model of Parkinson's Disease

Oueslati¹,

Paleologou²,

Schneider³

et al. 2012

J. Neurosci.

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Several lines of evidence suggest that phosphorylation of ␣-synuclein (␣-syn) at S87 or S129 may play an important role in regulating its aggregation, fibrillogenesis, Lewy body formation, and neurotoxicity in vivo. However, whether phosphorylation at these residues enhances or protects against ␣-syn toxicity in vivo remains unknown. In this study, we investigated the cellular and behavioral effect of overexpression of wild-type (WT), S87A, and S87E ␣-syn to block or to mimic S87 phosphorylation, respectively, in the substantia nigra of Wistar rats using recombinant adeno-associated vectors. Our results revealed that WT and S87A overexpression induced ␣-syn aggregation, loss of dopaminergic neurons, and fiber pathology. These neuropathological effects correlated well with the induction of hemi-parkinsonian motor symptoms. Strikingly, overexpression of the phosphomimic mutant S87E did not show any toxic effect on dopaminergic neurons and resulted in significantly less ␣-syn aggregates, dystrophic fibers, and motor impairment. Together, our data demonstrate, for the first time, that mimicking phosphorylation at S87 inhibits ␣-syn aggregation and protects against ␣-syn-induced toxicity in vivo, suggesting that phosphorylation at this residue would play an important role in controlling ␣-syn neuropathology. In addition, our results provide strong evidence for a direct correlation between ␣-syn-induced neurotoxicity, fiber pathology, and motor impairment and the extent of ␣-syn aggregation in vivo, suggesting that lowering ␣-syn levels and/or blocking its aggregation are viable therapeutic strategies for the treatment of Parkinson's disease and related synucleinopathies.

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“…And in the rat striatum, α ‐synuclein overexpression using viral vector‐mediated gene transfer results in decreased expression of PP2A B and C subunits as well as decreased PP2A activity. This effect is associated with increased α ‐synuclein phosphorylation and aggregation as well as neuronal cell death and inflammation 48. Interestingly, parkin, which is linked to recessively inherited PD due to loss of function mutations, reportedly prevents α ‐synuclein‐mediated reduction in PP2A expression and activity and mitigates the pathology induced by α ‐synculein 48.…”

Section: Discussionmentioning

confidence: 99%

“…This effect is associated with increased α ‐synuclein phosphorylation and aggregation as well as neuronal cell death and inflammation 48. Interestingly, parkin, which is linked to recessively inherited PD due to loss of function mutations, reportedly prevents α ‐synuclein‐mediated reduction in PP2A expression and activity and mitigates the pathology induced by α ‐synculein 48. The negative impact of impaired PP2A activity is also exerted on parkin functioning as well contributing to neuronal dyshomeostasis.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

Park

Lee

Park

et al. 2016

Ann Clin Transl Neurol

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ObjectiveProtein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α‐Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129, and PP2A containing a B55α subunit is a major phospho‐Ser129 phosphatase. The objective of this study was to investigate PP2A in α‐synucleinopathies.MethodsWe compared the state of PP2A methylation, as well as the expression of its methylating enzyme, leucine carboxyl methyltransferase (LCMT‐1), and demethylating enzyme, protein phosphatase methylesterase (PME‐1), in postmortem brains from PD and DLB cases as well as age‐matched Controls. Immunohistochemical studies and quantitative image analysis were employed.Results LCMT‐1 was significantly reduced in the substantia nigra (SN) and frontal cortex in both PD and DLB. PME‐1, on the other hand, was elevated in the PD SN. In concert with these changes, the ratio of methylated PP2A to demethylated PP2A was markedly decreased in PD and DLB brains in both SN and frontal cortex. No changes in total PP2A or total B55α subunit were detected.InterpretationThese findings support the hypothesis that PP2A dysregulation in α‐synucleinopathies may contribute to the accumulation of hyperphosphorylated α‐synuclein and to the disease process, raising the possibility that pharmacological means to enhance PP2A phosphatase activity may be a useful disease‐modifying therapeutic approach.

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Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model

Cited by 75 publications

References 50 publications

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Mimicking Phosphorylation at Serine 87 Inhibits the Aggregation of Human α-Synuclein and Protects against Its Toxicity in a Rat Model of Parkinson's Disease

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

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