The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

Hashimoto, Yuichi; Tsuji, Osahiko; Kanekura, Kohsuke; Aiso, Sadakazu; Niikura, Takako; Matsuoka, Masao; Nishimoto, Ikuo

doi:10.1074/jbc.m313630200

Cited by 6 publications

(2 citation statements)

References 61 publications

(57 reference statements)

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“…However, the relationship with AD and neurodegenerative disorders has been barely assessed. Only a few reports are found in the literature regarding AD and homeobox domain-containing genes, e.g., low expression of GAX gene, a regulator of vascular differentiation, in brain endothelial cells in AD [57], or GTX gene, a homeobox gene with neuroprotective properties [58]. Therefore, these findings open a new avenue for research to better understand the role of homeobox TFs in the AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation signature of human hippocampus in Alzheimer’s disease is linked to neurogenesis

et al. 2019

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Background Drawing the epigenome landscape of Alzheimer’s disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays. Results Up to 118 AD-related differentially methylated positions (DMPs) were identified in the AD hippocampus, and extended mapping of specific regions was obtained by bisulfite cloning sequencing. AD-related DMPs were significantly correlated with phosphorylated tau burden. Functional analysis highlighted that AD-related DMPs were enriched in poised promoters that were not generally maintained in committed neural progenitor cells, as shown by ChiP-qPCR experiments. Interestingly, AD-related DMPs preferentially involved neurodevelopmental and neurogenesis-related genes. Finally, InterPro ontology analysis revealed enrichment in homeobox-containing transcription factors in the set of AD-related DMPs. Conclusions These results suggest that altered DNA methylation in the AD hippocampus occurs at specific regulatory regions crucial for neural differentiation supporting the notion that adult hippocampal neurogenesis may play a role in AD through epigenetic mechanisms. Graphical abstract Electronic supplementary material The online version of this article (10.1186/s13148-019-0672-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

DNA methylation signature of human hippocampus in Alzheimer’s disease is linked to neurogenesis

et al. 2019

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“…Other significant genes, including RIPOR2 , FAM30A , DLX4 and LAT , are associated with inflammatory/immune processes and various cancer etiologies. Additionally, DLX4 is linked to neurogenesis and Alzheimer's disease [ 39 ]. In the same covariate analyses, when considering trend-significant associations, we identified genes such as TRIM10 and GAS7 , associated with schizophrenia [ 56 , 57 ], MACROH2A1 , related to autism-like behaviors [ 58 ], and ADORA2A , associated with anxiety disorders [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Unraveling epigenomic signatures and effectiveness of electroconvulsive therapy in treatment-resistant depression patients: a prospective longitudinal study

Carvalho Silva,

Martini,

Hohoff

et al. 2024

Clin Epigenet

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Background Electroconvulsive therapy (ECT) benefits patients with treatment-resistant depression (TRD), but the underlying biological processes are unclear. We conducted an epigenome-wide association study in 32 TRD patients undergoing ECT to depict ECT-associated methylation changes. Illness severity and ECT outcomes were assessed with the Montgomery–Åsberg Depression Rating Scale at baseline (T0) and 1 month after its end (T1). Methylation was profiled at T0 and T1 with the Illumina Infinium Methylation EPIC BeadChip array. Results Longitudinal T0–T1 analyses showed 3 differentially methylated probes (DMPs) with nominal p values ≤ 10−5, with 2 annotated in the genes CYB5B and PVRL4. Including covariates, we found 4 DMPs for symptoms variation, annotated in FAM20C, EPB41, OTUB1 and ADARB1, and 3 DMPs for response status, with 2 annotated in IQCE and FAM20C. Regional analysis revealed 54 differentially methylated regions (DMRs) with nominal p value area ≤ 0.05, with 9 presenting adjusted p-value area ≤ 0.10, annotated in MCF2L, SLC25A24, RUNX3, MIR637, FOXK2, FAM180B, POU6F1, ALS2CL and CCRL2. Considering covariates, we found 21 DMRs for symptoms variation and 26 DMRs for response (nominal p value area ≤ 0.05), with 4 presenting adjusted p-value area ≤ 0.10 for response, annotated in SNORD34, NLRP6, GALNT2 and SFT2D3. None remained significant after false discovery rate correction. Notably, ADARB1 variants are associated with suicide attempt in patients with psychiatric disorders, and SLC25A24 relates to conduct disorder. Several DMPs and DMRs are annotated in genes associated with inflammatory/immune processes. Longitudinal analyses on females (n = 22) revealed statistically significant DMRs (adjusted p value area ≤ 0.05) and trend-significant DMRs (adjusted p value area ≤ 0.07) for symptoms variation and response status, annotated in genes related to psychiatric disorders (ZFP57, POLD4, TRIM10, GAS7, ADORA2A, TOLLIP), trauma exposure (RIPOR2) and inflammatory/immune responses (LAT, DLX4, POLD4, FAM30A, H19). Pathway analysis on females revealed enrichment for transcriptional activity, growth factors, DNA maintenance, and immune pathways including IRF7 and IRF2. Conclusion Although no significant results were found for the whole cohort, the study provides insights into ECT-associated methylation changes, highlighting DMPs and DMRs related to ECT outcomes. Analyses on females revealed significant DMRs and pathways related to psychiatric disorders and inflammatory/immune processes.

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Cytotoxic mechanisms by M239V presenilin 2, a little‐analyzed Alzheimer's disease‐causative mutant

Abe

Hashimoto

Tomita

et al. 2004

J of Neuroscience Research

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Although neurotoxic functions are well characterized in familial Alzheimer's disease (FAD)-linked N141I mutant of presenilin (PS)2, little has been known about M239V-PS2, another established FAD-causative mutant. We found that expression of M239V-PS2 caused neuronal cytotoxicity. M239V-PS2 exerted three forms of cytotoxicity: one was sensitive to both an antioxidant glutathione-ethyl-ester (GEE) and a caspase inhibitor Ac-DEVD-CHO (DEVD); the second was sensitive to GEE but resistant to DEVD; and the third was resistant to both. The GEE/DEVD-sensitive cytotoxicity by M239V-PS2 was likely through NADPH oxidase and the GEE-sensitive/DEVD-resistant cytotoxicity through xanthine oxidase (XO). Both mechanisms by M239V-PS2 were suppressed by pertussis toxin (PTX) and were mediated by Galpha(o), but not by Galpha(i). Although Abeta1-43 itself induced no cytotoxicity, Abeta1-43 potentiated all three components of M239V-PS2 cytotoxicity. As these cytotoxic mechanisms by M239V-PS2 are fully shared with N141I-PS2, they are most likely implicated in the pathomechanism of FAD by PS2 mutations. Notably, cytotoxicity by M239V-PS2 could be inhibited by the combination of two clinically usable inhibitors of superoxide-generating enzymes, apocynin and oxypurinol.

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The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

Cited by 6 publications

References 61 publications

DNA methylation signature of human hippocampus in Alzheimer’s disease is linked to neurogenesis

DNA methylation signature of human hippocampus in Alzheimer’s disease is linked to neurogenesis

Unraveling epigenomic signatures and effectiveness of electroconvulsive therapy in treatment-resistant depression patients: a prospective longitudinal study

Cytotoxic mechanisms by M239V presenilin 2, a little‐analyzed Alzheimer's disease‐causative mutant

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