Iron-induced oxidative stress contributes to α-synuclein phosphorylation and up-regulation via polo-like kinase 2 and casein kinase 2

Wang, Ranran; Wang, You‐Cui; Qu, Le; Chen, Bingbing; Jiang, Hong; Song, Ning; Xie, Junxia

doi:10.1016/j.neuint.2019.02.016

Cited by 32 publications

(30 citation statements)

References 57 publications

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“…Furthermore, this elevation could be blocked by the NMDA receptor antagonist (Wu et al, 2007). Identical with protein level, transcription of the PLK2 gene is responsive to long-term potentiation and neuronal increased oxidative stress (Kauselmann et al, 1999;Wang et al, 2019). These results demonstrated that PLK2 might play a role in glutamateinduced excitotoxicity and provide a potential link between excitotoxic responses and Lewy pathology.…”

Section: Discussionmentioning

confidence: 83%

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

et al. 2020

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Glutamate overactivity in basal ganglia critically contributes to the exacerbation of dopaminergic neuron degeneration in Parkinson's disease (PD). Activation of group II metabotropic glutamate receptors (mGlu 2/3 receptors), which can decrease excitatory glutamate neurotransmission, provides an opportunity to slow down the degeneration of the dopaminergic system. However, the roles of mGlu 2/3 receptors in relation to PD pathology were partially recognized. By using mGlu 2/3 receptors agonist (LY354740) and mGlu 2/3 receptors antagonist (LY341495) in mice challenged with different cumulative doses of 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we demonstrated that systemic injection of LY354740 reduced the level of extracellular glutamate and the extent of nigro-striatal degeneration in both acute and sub-acute MPTP mice, while LY341495 amplified the lesions in sub-acute MPTP mice only. LY354740 treatment improved behavioral dysfunctions mainly in acute MPTP mice and LY341495 treatment seemed to aggravate motor deficits in subacute MPTP mice. In addition, ligands of mGlu 2/3 receptors also influenced the total amount of glutamate and dopamine in brain tissue. Interestingly, compared with normal mice, MPTPtreated mice abnormally up-regulated the expression of polo-like kinase 2 (PLK2)/pS129 asynuclein and phosphorylation of Fyn/N-methyl-D-aspartate receptor subunit 2A/2B (GluN2A/2B). Both acute and sub-acute MPTP mice treated with LY354740 dosedependently reduced all the above abnormal expression. Compared with MPTP mice treated with vehicle, mice pretreated with LY341495 exhibited much higher expression of p-Fyn Tyr416/p-GluN2B Tyr1472 and PLK2/pS129 a-synuclein in sub-acute MPTP mice models. Thus, our current data indicated that mGlu 2/3 receptors ligands could influence MPTP-induced toxicity, which supported a role for mGlu 2/3 receptors in PD pathogenesis.

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Section: Discussionmentioning

confidence: 83%

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

et al. 2020

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“…Oxidative stress is considered the most common trigger of α-Syn phosphorylation and misfolding [48]. Among several kinases that phosphorylate α-Syn at Ser-129 [47,49], polo-like kinase 2 and casein kinase 2 are upregulated by exposure to oxidative stress [47,50]. Both activated kinases significantly promote α-Syn phosphorylation levels in rat SN and SH-SY5Y cells following iron-induced oxidative stress, an effect inhibited by antioxidant N-acetyl-L-cysteine treatment [50].…”

Section: Discussionmentioning

confidence: 99%

“…Among several kinases that phosphorylate α-Syn at Ser-129 [47,49], polo-like kinase 2 and casein kinase 2 are upregulated by exposure to oxidative stress [47,50]. Both activated kinases significantly promote α-Syn phosphorylation levels in rat SN and SH-SY5Y cells following iron-induced oxidative stress, an effect inhibited by antioxidant N-acetyl-L-cysteine treatment [50]. Grassi et al have recently reported that non-fibrillar phosphorylated α-Syn derived from its PFF evokes mitochondrial cytochrome C release and oxidative stress [51], suggesting that oxidative stress also triggers the conversion of endogenous normal α-Syn to a pathological phosphorylated form and in turn promotes its propagation throughout the entire brain.…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Binding Protein 3 Enhances the Spreading and Toxicity of α-Synuclein in Mouse Brain

Yabuki

Matsuo

Kawahata

et al. 2020

IJMS

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Oligomerization and/or aggregation of α-synuclein (α-Syn) triggers α-synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies. It is known that α-Syn can spread in the brain like prions; however, the mechanism remains unclear. We demonstrated that fatty acid binding protein 3 (FABP3) promotes propagation of α-Syn in mouse brain. Animals were injected with mouse or human α-Syn pre-formed fibrils (PFF) into the bilateral substantia nigra pars compacta (SNpc). Two weeks after injection of mouse α-Syn PFF, wild-type (WT) mice exhibited motor and cognitive deficits, whereas FABP3 knock-out (Fabp3−/−) mice did not. The number of phosphorylated α-Syn (Ser-129)-positive cells was significantly decreased in Fabp3−/− mouse brain compared to that in WT mice. The SNpc was unilaterally infected with AAV-GFP/FABP3 in Fabp3−/− mice to confirm the involvement of FABP3 in the development of α-Syn PFF toxicity. The number of tyrosine hydroxylase (TH)- and phosphorylated α-Syn (Ser-129)-positive cells following α-Syn PFF injection significantly decreased in Fabp3−/− mice and markedly increased by AAV-GFP/FABP3 infection. Finally, we confirmed that the novel FABP3 inhibitor MF1 significantly antagonized motor and cognitive impairments by preventing α-Syn spreading following α-Syn PFF injection. Overall, FABP3 enhances α-Syn spreading in the brain following α-Syn PFF injection, and the FABP3 ligand MF1 represents an attractive therapeutic candidate for α-synucleinopathy.

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“…Iron has been primarily studied for its effects on PD pathology progression, particularly in its interaction with α-syn and induction of dopaminergic cell loss [352,431,432]. α-syn phosphorylation and expression were increased both in SH-SY5Y cells and in rats when exposed to higher amounts of iron, suggesting the key role of iron in regulating α-syn expression and S129 phosphorylation [433].…”

Section: Targeting Iron Homeostasismentioning

confidence: 99%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Iron-induced oxidative stress contributes to α-synuclein phosphorylation and up-regulation via polo-like kinase 2 and casein kinase 2

Cited by 32 publications

References 57 publications

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

Fatty Acid Binding Protein 3 Enhances the Spreading and Toxicity of α-Synuclein in Mouse Brain

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

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