Synphilin-1 has neuroprotective effects on MPP+-induced Parkinson’s disease model cells by inhibiting ROS production and apoptosis

Shishido, Takeo; Nagano, Yoshito; Araki, Mutsuko; Kurashige, Takashi; Obayashi, Hitomi; Nakamura, Takeshi; Takahashi, Tetsuya; Matsumoto, Masayasu; Makino, Hírofumi

doi:10.1016/j.neulet.2018.10.020

Cited by 40 publications

(12 citation statements)

References 30 publications

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“…Network pharmacological analysis and experimental studies revealed that the JNK/AP-1 signaling pathway mediates apoptosis in PD. Apoptosis inhibition may ameliorate DA neuron loss in PD (Shishido et al, 2018). The activation of JNK signaling has been shown to promote the apoptosis of dopaminergic neurons in the SNpc of PD rats (Borsello and Forloni, 2007;.…”

Section: Discussionmentioning

confidence: 99%

Compound Dihuang Granule Inhibits Nigrostriatal Pathway Apoptosis in Parkinson’s Disease by Suppressing the JNK/AP-1 Pathway

et al. 2021

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Compound Dihuang Granule (CDG) is widely used in traditional Chinese medicine (TCM) for the treatment of Parkinson’s disease (PD). It has been shown to alleviate PD symptoms. However, the molecular mechanisms of its action have not been established. To establish the molecular mechanisms of CDG against PD, we used TCM network pharmacology methods to predict its molecular targets and signaling pathways, followed by experimental validation. The Core Protein protein interaction (PPI) network of the 150 intersections between CDG and PD-related genes, comprising 23 proteins, including CASP3 (caspase-3), MAPK8 (JNK), FOS (c-Fos), and JUN (c-Jun). KEGG and GO analyses revealed that apoptotic regulation and MAPK signaling pathways were significantly enriched. Since c-Jun and c-Fos are AP-1 subunits, an important downstream JNK effector, we investigated if the JNK/AP-1 pathway influences CDG against apoptosis through the nigrostriatal pathways in PD rat models. Molecular docking analysis found that the top three bioactive compounds exhibiting the highest Degree Centrality following online database and LC-MS analysis had high affinities for JNK. Experimental validation analysis showed that CDG decreased the number of rotating laps and suppressed the levels of phosphorylated c-Jun, c-Fos, and JNK, as well as the number of TUNEL positive cells and the cleaved caspase-3 level in the nigrostriatal pathway. Furthermore, CDG treatment elevated the number of TH neurons, TH expression level, and Bcl-2/Bax protein ratio in a 6-OHDA-induced PD rat. These findings are in tandem with those obtained using SP600125, a specific JNK inhibitor. In conclusion, CDG suppresses the apoptosis of the nigrostriatal pathway and relieves PD symptoms by suppressing the JNK/AP-1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Compound Dihuang Granule Inhibits Nigrostriatal Pathway Apoptosis in Parkinson’s Disease by Suppressing the JNK/AP-1 Pathway

et al. 2021

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“…Synphilin, is a protein located in the Lewy bodies or in the cytoplasm that interacts with α-syn. Although early studies have suggested that this protein may increase the tendency to form aggregates and inclusion bodies of α-syn protein, on the contrary recent studies have shown that this protein is neuroprotective [53,54].…”

Section: Post-translational Modifications Of Alpha Synuclein Proteinmentioning

confidence: 90%

An Overview of Alpha Synuclein Protein and Its Role in Parkinson’s disease

Kaya

Atilla

2021

Acta Medica

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Parkinson’s disease is the most common age-related motor movement disorder. Pathological changes in Parkinson’s disease are the loss of melanin-containing dopaminergic neurons and the detection of inclusion bodies in the cells, which contain alpha-synuclein and ubiquitinated proteins, called as Lewy bodies. In this review; the structure of Lewy bodies, structural features and intracellular localization of α-synuclein protein, intracellular functions and intercellular spread of α-synuclein protein are discussed. The physiological and pathologic features of α-synuclein protein are reviewed based mostly upon review of the literature. α-synuclein has significant functions especially at central nervous system. α-synuclein is a protein that can be found in various areas within the cell, particularly in the presynaptic axon terminals. Under pathologic conditions, cellular accumulation of misfolded α-synuclein oligomers and aggregates are observed in a group of neurodegenerative diseases called synucleinopathies. The mechanisms of how α-synuclein protein takes part in the neurodegeneration process and physiologic roles of the protein have not been fully elucidated yet. It’s important to unravel the secrets of this protein and understand its behaviours in order to improve existing treatment protocols and also to develop new and more effective treatments for Parkinson’s Disease.

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“…The newly synthesized or taken up DA is stored in vesicles with the aid of vesicular monoaminergic transporter-2 (Slc18a2) [40]. Pitx3 has been implicated in the proper development of mild brain DA neurons in the substantia nigra pars compacta, and it may directly activate transcription of Slc18a2 and Slc6a3 [41]. Synphilin-1, a cytoplasmic protein encoded by Sncaip, interacts with αsynuclein, the main constituents of Lewy bodies, and plays an important role in the pathology of PD.…”

Section: Discussionmentioning

confidence: 99%

Molecular Regulatory Mechanism and Toxicology of Neurodegenerative Processes in MPTP/Probenecid-Induced Progressive Parkinson’s Disease Mice Model Revealed by Transcriptome

et al. 2020

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Parkinson’s disease (PD) is a neurodegenerative disease caused by a variety of unclear complex pathogenic factors. The 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced progressive PD mice is a well-recognized classic model for studying PD, but the molecular toxicology of this model is still unclear. Here, for the first time, we report gradual neurodegenerative processes in MPTP/p-induced progressive PD mice model using RNA-seq. Transcriptional responses are orchestrated to regulate the expression of many genes in substantia nigra, such as Ntf3, Pitx3, Th, and Drd2, leading to the degeneration of dopaminergic neurons at last. We proposed that the established model could be divided into three phases based on their molecular toxicological features: “the stress response phase” which maintained the microenvironment homeostasis, “the pre-neurodegenerative phase” which demonstrated observed MPTP/p cytotoxicity and gradual degeneration of dopaminergic neurons, and “the neurodegenerative phase” which reflected distinct damage and dopaminergic neuron apoptotic process. Glia cells exhibited a certain protective effect on dopaminergic neurons in 3rd and 6th MPTP/p-induced cytotoxicity. But in 10th MPTP/p injection, glia cells play a promoting role in PD and tissue damages caused by oxidative stress. This study also indicated that the substantia nigra of PD mice showed unique patterns of changes at each stage. Moreover, neurotrophic signaling pathway, ECM-receptor interaction, oxidative phosphorylation, apoptosis and necroptosis were enriched at 3rd and 6th MPTP/p injection, which might be associated with the PD progress. This study provided an extensive data set of molecular toxicology for elucidating of PD progression and offered comprehensive theoretical knowledge for the development of new therapy.

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Synphilin-1 has neuroprotective effects on MPP+-induced Parkinson’s disease model cells by inhibiting ROS production and apoptosis

Abstract: Synphilin-1 has neuroprotective effects on MPP +-induced Parkinson's disease model cells by inhibiting ROS production and apoptosis

Cited by 40 publications

References 30 publications

Compound Dihuang Granule Inhibits Nigrostriatal Pathway Apoptosis in Parkinson’s Disease by Suppressing the JNK/AP-1 Pathway

Compound Dihuang Granule Inhibits Nigrostriatal Pathway Apoptosis in Parkinson’s Disease by Suppressing the JNK/AP-1 Pathway

An Overview of Alpha Synuclein Protein and Its Role in Parkinson’s disease

Molecular Regulatory Mechanism and Toxicology of Neurodegenerative Processes in MPTP/Probenecid-Induced Progressive Parkinson’s Disease Mice Model Revealed by Transcriptome

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