Mitochondrial dysfunction in GnRH neurons impaired GnRH production

Kagawa, Yoshiteru; Umaru, Banlanjo Abdulaziz; Shil, Subrata Kumar; Hayasaka, Ken; Zama, Ryo; Kobayashi, Yuta; Miyazaki, Hirofumi; Kobayashi, Shuhei; Suzuki, Chitose; Katori, Yukio; Abe, Takaaki; Owada, Yuji

doi:10.1016/j.bbrc.2020.07.090

Cited by 9 publications

(5 citation statements)

References 21 publications

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“… 55 Further, studies demonstrated that impaired GnRH production is directly linked to oxidative stress and mitochondrial dysfunction in neurons. 56 , 57 Another significantly enriched pathway is the gap junction that is involved in the pathogenesis of AD and PD. 58 , 59 For instance, Angeli et al, 2020, demonstrated the altered expression of glial gap junction proteins, namely, Cx43, Cx30, and Cx47, in the 5XFAD model of AD, 60 whereas Maulik et al, 2020, concluded that Aβ regulates the gap junction protein connexin 43 in cultured primary astrocytes.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Similarly, a study concluded that the balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in spiny neurons, where D1R and A2AR agonist enhanced PKA-mediated Rap1 phosphorylation in vivo and in vitro . Further, studies demonstrated that impaired GnRH production is directly linked to oxidative stress and mitochondrial dysfunction in neurons. , Another significantly enriched pathway is the gap junction that is involved in the pathogenesis of AD and PD. , For instance, Angeli et al, 2020, demonstrated the altered expression of glial gap junction proteins, namely, Cx43, Cx30, and Cx47, in the 5XFAD model of AD, whereas Maulik et al, 2020, concluded that Aβ regulates the gap junction protein connexin 43 in cultured primary astrocytes . Consistent with this, the results demonstrated the importance of CDC42, TUBB4B, and FGFR1 in the pathogenesis of AD and PD.…”

Section: Results and Discussionmentioning

confidence: 99%

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CREB1^K292 and HINFP^K330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

Gupta

Kumar

2021

ACS Omega

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Integration of omics data and deciphering the mechanism of a biological regulatory network could be a promising approach to reveal the molecular mechanism involved in the progression of complex diseases, including Alzheimer’s and Parkinson’s. Despite having an overlapping mechanism in the etiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the exact mechanism and signaling molecules behind them are still unknown. Further, the acetylation mechanism and histone deacetylase (HDAC) enzymes provide a positive direction toward studying the shared phenomenon between AD and PD pathogenesis. For instance, increased expression of HDACs causes a decrease in protein acetylation status, resulting in decreased cognitive and memory function. Herein, we employed an integrative approach to analyze the transcriptomics data that established a potential relationship between AD and PD. Data preprocessing and analysis of four publicly available microarray datasets revealed 10 HUB proteins, namely, CDC42, CD44, FGFR1, MYO5A, NUMA1, TUBB4B, ARHGEF9, USP5, INPP5D, and NUP93, that may be involved in the shared mechanism of AD and PD pathogenesis. Further, we identified the relationship between the HUB proteins and transcription factors that could be involved in the overlapping mechanism of AD and PD. CREB1 and HINFP were the crucial regulatory transcription factors that were involved in the AD and PD crosstalk. Further, lysine acetylation sites and HDAC enzyme prediction revealed the involvement of 15 and 27 potential lysine residues of CREB1 and HINFP, respectively. Our results highlighted the importance of HDAC1(K292) and HDAC6(K330) association with CREB1 and HINFP, respectively, in the AD and PD crosstalk. However, different datasets with a large number of samples and wet lab experimentation are required to validate and pinpoint the exact role of CREB1 and HINFP in the AD and PD crosstalk. It is also possible that the different datasets may or may not affect the results due to analysis parameters. In conclusion, our study potentially highlighted the crucial proteins, transcription factors, biological pathways, lysine residues, and HDAC enzymes shared between AD and PD at the molecular level. The findings can be used to study molecular studies to identify the possible relationship in the AD–PD crosstalk.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

CREB1^K292 and HINFP^K330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

Gupta

Kumar

2021

ACS Omega

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“…To obtain FABP7 knock‐out (KO) cells in U251 cells, we performed Crispr/Cas9 editing as previously described [ 17 ]. Briefly, sgRNA expression plasmid was constructed using CHOPCHOP ( https://chopchop.cbu.uib.no/ ), with selected target sites within exon 1 of the human FABP7 gene.…”

Section: Methodsmentioning

confidence: 99%

Nuclear FABP7 regulates cell proliferation of wild‐type IDH1 glioma through caveolae formation

et al. 2021

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Isocitrate dehydrogenase 1 (IDH1) is a key enzyme in cellular metabolism. IDH1 mutation (IDH1mut) is the most important genetic alteration in lower grade glioma, whereas glioblastoma (GB), the most common malignant brain tumor, often has wild‐type IDH1 (IDH1wt). Although there is no effective treatment yet for neither IDH1wt nor IDHmut GB, it is important to note that the survival span of IDH1wt GB patients is significantly shorter than those with IDH1mut GB. Thus, understanding IDH1wt GB biology and developing effective molecular‐targeted therapies is of paramount importance. Fatty acid‐binding protein 7 (FABP7) is highly expressed in GB, and its expression level is negatively correlated with survival in malignant glioma patients; however, the underlying mechanisms of FABP7 involvement in tumor proliferation are still unknown. In this study, we demonstrate that FABP7 is highly expressed and localized in nuclei in IDH1wt glioma. Wild‐type FABP7 (FABP7wt) overexpression in IDH1wt U87 cells increased cell proliferation rate, caveolin‐1 expression, and caveolae/caveosome formation. In addition, FABP7wt overexpression increased the levels of H3K27ac on the caveolin‐1 promoter through controlling the nuclear acetyl‐CoA level via the interaction with ACLY. Consistent results were obtained using a xenograft model transplanted with U87 cells overexpressing FABP7 . Interestingly, in U87 cells with mutant FABP7 overexpression, both in vitro and in vivo phenotypes shown by FABP7wt overexpression were disrupted. Furthermore, IDH1wt patient GB showed upregulated caveolin‐1 expression, increased levels of histone acetylation, and increased levels of acetyl‐CoA compared with IDH1mut patient GB. Taken together, these data suggest that nuclear FABP7 is involved in cell proliferation of GB through caveolae function/formation regulated via epigenetic regulation of caveolin‐1, and this mechanism is critically important for IDH1wt tumor biology.

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“…Oxygen consumption rate (OCR) of Neuro-2a cells was measured according to the manufacturer’s protocols and previous published article 50 . Briefly, transfected cells were seeded in XF24 culture plate, induced differentiation and cultured in assay medium containing 25 mM glucose, 2 mM L-glutamine, 1 mM sodium pyruvate and 30 mM NaCl (pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

Ndufs4 ablation decreases synaptophysin expression in hippocampus

Shil

Kagawa

Umaru

et al. 2021

Sci Rep

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Altered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation in human is associated with Leigh syndrome. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons, and GFAP-positive astrocytes in WT mouse hippocampus, we found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Although there was no change in the number of NeuN positive neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was significantly decreased. To investigate the detailed mechanism, we silenced Ndufs4 in Neuro-2a cells and we observed shorter neurite lengths with decreased expression of synaptophysin. Furthermore, western blot analysis for phosphorylated extracellular regulated kinase (pERK) revealed that Ndufs4 silencing decreases the activity of ERK signalling. These results suggest that Ndufs4-modulated mitochondrial activity may be involved in neuroplasticity via regulating synaptophysin expression.

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Mitochondrial dysfunction in GnRH neurons impaired GnRH production

Cited by 9 publications

References 21 publications

CREB1^K292 and HINFP^K330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

CREB1^K292 and HINFP^K330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

Nuclear FABP7 regulates cell proliferation of wild‐type IDH1 glioma through caveolae formation

Ndufs4 ablation decreases synaptophysin expression in hippocampus

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Mitochondrial dysfunction in GnRH neurons impaired GnRH production

Cited by 9 publications

References 21 publications

CREB1K292 and HINFPK330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

CREB1K292 and HINFPK330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

Nuclear FABP7 regulates cell proliferation of wild‐type IDH1 glioma through caveolae formation

Ndufs4 ablation decreases synaptophysin expression in hippocampus

Contact Info

Product

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CREB1^K292 and HINFP^K330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

CREB1^K292 and HINFP^K330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease