Impact of Fatty Acid-Binding Proteins in α-Synuclein-Induced Mitochondrial Injury in Synucleinopathy

Cheng, An; Jia, Wenbin; Kawahata, Ichiro; Fukunaga, Kohji

doi:10.3390/biomedicines9050560

Cited by 13 publications

(7 citation statements)

References 149 publications

(191 reference statements)

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“…Increased concentrations of B-FABP are associated with human brain tumors (e.g., glioblastoma and astrocytoma), neurodegenerative diseases (Alzheimer’s disease and PD), and other cognitive dysfunctions ( Choromańska et al, 2011 ). A series of studies suggest that FABP3, FABP5, and FABP7 play important roles in α-synuclein oligomerization and migration, trigger the loss of neuronal mitochondrial function, and even interact with VDAC-1 to modulate the formation of channel pores in the mitochondrial membrane ( Kawahata et al, 2019 ; Matsuo et al, 2019 ; Cheng et al, 2021 ; Kawahata and Fukunaga, 2022 ). Thus, FABP is considered a promising therapeutic target for α-synucleinopathies ( Kawahata and Fukunaga, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s mouse model

Weng

Song

et al. 2023

Front. Neurosci.

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IntroductionParkinson’s disease (PD), as a common neurodegenerative disease, currently has no effective therapeutic approaches to delay or stop its progression. There is an urgent need to further define its pathogenesis and develop new therapeutic targets. An increasing number of studies have shown that members of the sirtuin (SIRT) family are differentially involved in neurodegenerative diseases, indicating their potential to serve as targets in therapeutic strategies. Mitochondrial SIRT4 possesses multiple enzymatic activities, such as deacetylase, ADP ribosyltransferase, lipoamidase, and deacylase activities, and exhibits different enzymatic activities and target substrates in different tissues and cells; thus, mitochondrial SIRT4 plays an integral role in regulating metabolism. However, the role and mechanism of SIRT4 in PD are not fully understood. This study aimed to investigate the potential mechanism and possible regulatory targets of SIRT4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice.MethodsThe expression of the SIRT4 protein in the MPTP-induced PD mouse mice or key familial Parkinson disease protein 7 knockout (DJ-1 KO) rat was compared against the control group by western blot assay. Afterwards, quantitative proteomics and bioinformatics analyses were performed to identify altered proteins in the vitro model and reveal the possible functional role of SIRT4. The most promising molecular target of SIRT4 were screened and validated by viral transfection, western blot assay and reverse transcription quantitative PCR (RT-qPCR) assays.ResultsThe expression of the SIRT4 protein was found to be altered both in the MPTP-induced PD mouse mice and DJ-1KO rats. Following the viral transfection of SIRT4, a quantitative proteomics analysis identified 5,094 altered proteins in the vitro model, including 213 significantly upregulated proteins and 222 significantly downregulated proteins. The results from bioinformatics analyses indicated that SIRT4 mainly affected the ribosomal pathway, propionate metabolism pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway and peroxisome pathway in cells, and we screened 25 potential molecular targets. Finally, only fatty acid binding protein 4 (FABP4) in the PPAR signaling pathway was regulated by SIRT4 among the 25 molecules. Importantly, the alterations in FABP4 and PPARγ were verified in the MPTP-induced PD mouse model.DiscussionOur results indicated that FABP4 in the PPAR signaling pathway is the most promising molecular target of SIRT4 in an MPTP-induced mouse model and revealed the possible functional role of SIRT4. This study provides a reference for future drug development and mechanism research with SIRT4 as a target or biomarker.

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Section: Introductionmentioning

confidence: 99%

Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s mouse model

Weng

Song

et al. 2023

Front. Neurosci.

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“…We also demonstrated that the increase in CaMKII autophosphorylation levels induced by QNP stimulation was significantly inhibited by MF1 treatment, which was observed in cultured NAc slices from WT but not D2R null mice, suggesting that MF1 prevents CaMKII autophosphorylation by inhibiting D2Rs. FABP3 interacts and colocalizes with D2LR in vitro and in vivo [ 30 , 31 , 58 , 59 ]. Therefore, MF1, an FABP3 inhibitor, may also inhibit D2R/FABP3 function.…”

Section: Discussionmentioning

confidence: 99%

Amelioration of Nicotine-Induced Conditioned Place Preference Behaviors in Mice by an FABP3 Inhibitor

Jia

Kawahata

Cheng

et al. 2023

IJMS

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We previously demonstrated that fatty acid-binding protein 3 null (FABP3−/−) mice exhibit resistance to nicotine-induced conditioned place preference (CPP). Here, we confirm that the FABP3 inhibitor, MF1 ((4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid), successfully reduces nicotine-induced CPP scores in mice. MF1 (0.3 or 1.0 mg/kg) was orally administered 30 min before nicotine, and CPP scores were assessed in the conditioning, withdrawal, and relapse phases. MF1 treatment decreased CPP scores in a dose-dependent manner. Failure of CPP induction by MF1 (1.0 mg/kg, p.o.) was associated with the inhibition of both CaMKII and ERK activation in the nucleus accumbens (NAc) and hippocampal CA1 regions. MF1 treatment reduced nicotine-induced increases in phosphorylated CaMKII and cAMP-response element-binding protein (CREB)-positive cells. Importantly, the increase in dopamine D2 receptor (D2R) levels following chronic nicotine exposure was inhibited by MF1 treatment. Moreover, the quinpirole (QNP)-induced increase in the level of CaMKII and ERK phosphorylation was significantly inhibited by MF1 treatment of cultured NAc slices from wild type (WT) mice; however, QNP treatment had no effect on CaMKII and ERK phosphorylation levels in the NAc of D2R null mice. Taken together, these results show that MF1 treatment suppressed D2R/FABP3 signaling, thereby preventing nicotine-induced CPP induction. Hence, MF1 can be used as a novel drug to block addiction to nicotine and other drugs by inhibiting the dopaminergic system.

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“…FABP3, FABP5, and FABP7 are expressed in the brain. Many studies have linked these three FABP subtypes to neuronal damage and inflammatory pathways in various neurodegenerative disorders [ [15] , [16] , [17] , [18] , [19] ]. Abnormal FABP expression occurs in patients with neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.…”

Section: Introductionmentioning

confidence: 99%

Fatty acid-binding proteins 3 and 5 are involved in the initiation of mitochondrial damage in ischemic neurons

et al. 2023

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Impact of Fatty Acid-Binding Proteins in α-Synuclein-Induced Mitochondrial Injury in Synucleinopathy

Cited by 13 publications

References 149 publications

Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s mouse model

Proteomic profiling reveals the potential mechanisms and regulatory targets of sirtuin 4 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s mouse model

Amelioration of Nicotine-Induced Conditioned Place Preference Behaviors in Mice by an FABP3 Inhibitor

Fatty acid-binding proteins 3 and 5 are involved in the initiation of mitochondrial damage in ischemic neurons

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