Inhibition of MPTP-induced α-synuclein oligomerization by fatty acid-binding protein 3 ligand in MPTP-treated mice

Matsuo, Keitaro; Cheng, An; Yabuki, Yasushi; Takahata, Ibuki; Miyachi, Hiroyuki; Fukunaga, Kohji

doi:10.1016/j.neuropharm.2019.03.029

Cited by 35 publications

(35 citation statements)

References 59 publications

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“…In the current study, p-α-Synuclein and α-Synuclein protein were increased in SN and Hippo areas ( Figure 1A and B), which is consistent with former studies. 23,33 In addition, the upregulated p-α-Synuclein mainly localized in the limbic systems such as cortex, polymorph layer of hippocampal, amygdala and VTA (Figure 2A and B). In the cellular level, the p-α-Synuclein localized in the nucleus and cytoplasm in cortex, amygdala, VTA and pyramidal layer of hippocampal CA3, and neurites in polymorph layer of hippocampal CA3.…”

Section: Discussionmentioning

confidence: 99%

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Hu¹,

Hu²,

Liu³

et al. 2020

NDT

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Parkinson's disease (PD) is the second most common neurodegenerative disease. The α-Synuclein is a major component of Lewy bodies and Lewy neurites, the pathologic hallmark of PD. It is known that α-Synuclein is phosphorylated (p-α-Synuclein) in PD and tau-hyperphosphorylation (p-Tau) is also a pathologic feature of PD. However, the relationship between p-Synuclein and p-Tau in PD is not clear, in particular in the MPTP model of PD. The purpose of this study was to reveal their relationship in the mouse MPTP model. Methods: Firstly, the p-α-Synuclein, α-Synuclein, p-Tau and Tau protein levels were analyzed. Then, GSK3β activation was determined using immunoblot and immunohistochemical staining. Finally, the dopaminergic neurodegeneration was assessed using Tyrosine Hydroxylase (TH) staining and retrograde labeling and microglial marker were labeled. Microglial activation and nigrostriatal pathway degeneration were observed. Results: The results showed that p-α-Synuclein, α-Synuclein, p-Tau and Tau were upregulated in both hippocampus and substantia nigra of the PD mouse model. Furthermore, p-α-Synuclein and p-Tau were localized in the same regions of substantial nigra (SN) and dentate gyrus (DG) of hippocampus (Hippo). The activated form of GSK3β (phosphor GSK3β Y216) was increased in multiple brain areas. The GSK3β inhibitor AZD1080 injected in MPTP mice suppressed the expression of p-Tau and p-GSK3β and improved motor functions. Conclusion: These findings revealed that p-α-Synuclein and p-Tau proteins are key pathological events leading to neurodegeneration and motor dysfunctions in the mouse MPTP model of PD. Our data suggest that the interference with the GSK3β activity may be an effective approach for the treatment of PD.

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Section: Discussionmentioning

confidence: 99%

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Hu¹,

Hu²,

Liu³

et al. 2020

NDT

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“…There is increasing evidence that autophagy exerts vital effect on the innate immune response. In addition, autophagy-related pathways are implicated in the regulation of NLRP3 inflammasome activation (10)(11)(12). It has been reported in the literature that α-synuclein can promote immune activation in PD patients.…”

Section: Introductionmentioning

confidence: 99%

α-synuclein promotes progression of Parkinson's disease by upregulating autophagy signaling pathway to activate NLRP3 inflammasome

et al. 2019

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Mechanism by which α-synuclein affects the progression of Parkinson's disease through Pyrin Domain Containing Protein 3 (NLRP3) was explored. Peripheral blood plasma of 40 Parkinson's disease patients and 40 normal healthy people attending the department of neurology of the Third Affiliated Hospital of Qiqihar Medical University were collected from March 2018 to January 2019. The expression levels of oligomers, phosphorylated α-synuclein, interleukin-1β (IL-1β), interleukin-6 (IL-6) and transforming growth factor-α (TGF-α) in plasma were detected by ELISA. Astrocytes in mouse brain tissues were extracted by primary culture method, the cells were divided into drug group and the drug + inhibitor group. After adding 0, 5, 10 and 20 µg oligomerized α-synuclein or 5 mM autophagy inhibitor 3-Methyladenine (3-MA), the expression level of NLRP3, caspase-1, IL-1β and Atg5 proteins in the cells was detected. The expression level of IL-1β in peripheral blood of PD patients was significantly increased (0.604±0.136 µmol/l vs. 1.876±0.327 µmol/l, P=0.002), while there was no significant difference between IL-6 and TGF-α. Both oligomers (0.171±0.045 µmol/l vs. 0.676±0.084 µmol/l, P<0.0001) and phosphorylated α-synuclein (0.128±0.041 µmol/l vs. 0.849±0.108 µmol/l, P<0.0001) in peripheral blood of PD patients were significantly elevated. The expression levels of NLRP3, caspase-1 and IL-1β in mouse astrocytes all increased with the increase of the concentration of oligomerized α-synuclein, and Atg5 protein expression also increased gradually with the concentration, and reached the highest level when the concentration was 10 µg/ml. The expression levels of NLRP3, caspase-1 and IL-1β were inhibited after the addition of autophagy inhibitor 3-MA. α-synuclein mediates the activation of NLRP3 inflammasome in PD patients by up regulating Atg5 protein expression.

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“…We used a dose of MF1 of 1.0 mg/kg because MF1 (1.0 mg/kg, p.o.) is enough to attenuate MPTP-induced neurotoxicity in mice [42].…”

Section: Drug Administrationmentioning

confidence: 99%

“…The present study assessed its ameliorative effects in synucleinopathy model mice using bilateral injection with mouse α-Syn PFF into the SNpc. The therapeutic dose of MF1 was defined by a previous study that used PD model mice [42], and mice injected with human or mouse α-Syn PFF into the bilateral SNpc were used to evaluate the effects of MF1. We observed a significant group effect on the number of phosphorylated α-Syn 3 /mm 2 , p < 0.01 versus human α-Syn PFF-injected mice; cortex: 147.6 ± 37.9 /mm 2 , p < 0.05 vs. human α-Syn PFF-injected mice) ( Figure 5A,B).…”

Section: The Selective Fabp3 Inhibitor Mf1 Prevents Spreading Of Phosmentioning

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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Inhibition of MPTP-induced α-synuclein oligomerization by fatty acid-binding protein 3 ligand in MPTP-treated mice

Cited by 35 publications

References 59 publications

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

α-synuclein promotes progression of Parkinson's disease by upregulating autophagy signaling pathway to activate NLRP3 inflammasome

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

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