α-Synuclein and Lewy pathology in Parkinson's disease

Kalia, Lorraine V.; Kalia, Suneil K.

doi:10.1097/wco.0000000000000215

Cited by 85 publications

(62 citation statements)

References 40 publications

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“…In the brain, α-synuclein (α-syn) exists in monomeric, oligomeric and more-aggregated forms, such as fibrils 19 . The factors governing the transition between these forms in vivo are not known, and how these forms might spread is unresolved.…”

Section: Does Lp Retrogradely Spread In Cpd?mentioning

confidence: 99%

Selective neuronal vulnerability in Parkinson disease

2017

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Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms. Moreover, the correlation between LP and neuronal death is weak. In this Review, we briefly discuss the evidence for and against the spreading LP model, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.

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Section: Does Lp Retrogradely Spread In Cpd?mentioning

confidence: 99%

Selective neuronal vulnerability in Parkinson disease

2017

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“…From theoretical perspective, the NAC terminus of α-Syn is a hydrophobic region, and it can bind to many moleculars and regulate their activity [6,9,44]. Here, we found that the NAC domain of α-Syn could interact with PP2A Cα and upregulate its activity.…”

Section: Discussionmentioning

confidence: 60%

“…As we know, α-Syn is a natively unfolded protein with a tendency to aggregate by the hydrophobic interaction [8,13,44]. After aggregation, the hydrophobic domain of α-Syn may be blocked, so α-Syn aggregates should less upregulate the PP2A activity than monomers.…”

Section: Blocking the Nac Domain Of α-Syn Declined Its Regulating Effmentioning

confidence: 99%

The Molecular Mechanism of Alpha-Synuclein Dependent Regulation of Protein Phosphatase 2A Activity

Yan

Yuan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Alpha-synuclein (α-Syn) is a neuronal protein that is highly implicated in Parkinson’s disease (PD), and protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that is associated with neurodegenerative diseases, such as PD. α-Syn can directly upregulate PP2A activity, but the underling mechanism remains unclear. Therefore, we investigated the molecular mechanism of α-Syn regulating PP2A activity. Methods: α-Syn and its truncations were expressed in E.coli, and purified by affinity chromatography. PP2A Cα and its mutants were expressed in recombinant baculovirus, and purified by affinity chromatography combined with gel filtration chromatography. The interaction between α-Syn and PP2A Cα was detected by GST pull-down assay. PP2A activity was investigated by the colorimetric assay. Results: The hydrophobic non-amyloid component (NAC) domain of α-Syn interacted with PP2A Cα and upregulated its activity. α-Syn aggregates reduced its ability to upregulate PP2A activity, since the hydrophobic domain of α-Syn was blocked during aggregation. Furthermore, in the hydrophobic center of PP2A Cα, the residue of I123 was responsible for PP2A to interact with α-Syn, and its hydrophilic mutation blocked its interaction with α-Syn as well as its activity upregulation by α-Syn. Conclusions: α-Syn bound to PP2A Cα by the hydrophobic interaction and upregulated its activity. Blocking the hydrophobic domain of α-Syn or hydrophilic mutation on the residue I123 in PP2A Cα all reduced PP2A activity upregulation by α-Syn. Overall, we explored the mechanism of α-Syn regulating PP2A activity, which might offer much insight into the basis underlying PD pathogenesis.

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“…Current research indicates that multiple factors involved in the pathogenesis of PD, including spontaneous process of cells, namely autophagy lysosome dysfunction [3], proteasome dysfunction, mitochondrial dysfunction [4]; non-spontaneous process of cells, such as neuroinflammatory reactions, apoptosis, oxidative stress and loss of nutritional support [5,6]. There are many crossing signal system between the various molecular mechanisms [7,8].…”

mentioning

confidence: 99%

“…Initial characterization of the pathology in PD (Parkinson's disease) focused attention on the presence of the Lewy body in remaining dopaminergic neurons and the role played by melanin [1,2]. Current research indicates that multiple factors involved in the pathogenesis of PD, including spontaneous process of cells, namely autophagy lysosome dysfunction [3], proteasome dysfunction, mitochondrial dysfunction [4]; non-spontaneous process of cells, such as neuroinflammatory reactions, apoptosis, oxidative stress and loss of nutritional support [5,6].…”

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confidence: 99%

The Potential Targets of Chinese Medicines in the Treatment of Parkinson’s Disease: Old Wine in New Bottles

Zhang¹,

Li²,

Wang³

et al. 2016

JPP

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This article systematically reviews the present research situation of the pathogenesis of PD (Parkinson's disease) and our recent research over the past decade, to discuss the potential targets of many TCM (traditional Chinese medicines) in prevention and treatment of PD, such as against oxidative stress (Astragaloside, protocatechuic aldehyde, Liu-Wei-Di-Huang), anti-apoptosis (Geniposide, Zhichan powder), improve mitochondrial function (Paeoniflorin, Da-Bu-Yin-Wan), inhibition of protein aggregation (Panax ginseng, Irisflorentin), induce autophagy (piperine, Paeoniflorin), and many other mechanisms and multiple effectiveness (Saponins, Acanthopanax). With the research and development in PD pathogenesis and clarifying the targets of a variety of traditional Chinese medicine, especially its monomeric components, the development of traditional Chinese medicine in prevention and treatment of PD will have very broad application value and prospect.

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α-Synuclein and Lewy pathology in Parkinson's disease

Cited by 85 publications

References 40 publications

Selective neuronal vulnerability in Parkinson disease

Selective neuronal vulnerability in Parkinson disease

The Molecular Mechanism of Alpha-Synuclein Dependent Regulation of Protein Phosphatase 2A Activity

The Potential Targets of Chinese Medicines in the Treatment of Parkinson’s Disease: Old Wine in New Bottles

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