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Keywords = brain gene expression proteins

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17 pages, 2157 KiB  
Article
Antioxidant, Osteogenic, and Neuroprotective Effects of Homotaurine in Aging and Parkinson’s Disease Models
by Arianna Minoia, Francesca Cristiana Piritore, Silvia Bolognin, João Pessoa, Bruno Bernardes de Jesus, Natascia Tiso, Maria Grazia Romanelli, Jens Christian Schwamborn, Luca Dalle Carbonare and Maria Teresa Valenti
Antioxidants 2025, 14(3), 249; https://doi.org/10.3390/antiox14030249 - 21 Feb 2025
Viewed by 175
Abstract
Aging is associated with the accumulation of cellular damage due to oxidative stress and chronic low-grade inflammation, collectively referred to as “inflammaging”. This contributes to the functional decline in various tissues, including the brain and skeletal system, which closely interplay. Mesenchymal stem cells [...] Read more.
Aging is associated with the accumulation of cellular damage due to oxidative stress and chronic low-grade inflammation, collectively referred to as “inflammaging”. This contributes to the functional decline in various tissues, including the brain and skeletal system, which closely interplay. Mesenchymal stem cells (MSCs), known for their regenerative potential and ability to modulate inflammation, offer a promising therapeutic approach to counteract aging-related declines. In this study, we investigated the effects of homotaurine (a small molecule with neuroprotective properties) on MSCs and its effects on osteogenesis. We found that homotaurine treatment significantly reduced reactive oxygen species (ROS) levels, improved MSC viability, and modulated key stress response pathways, including the sestrin 1 and p21 proteins. Furthermore, homotaurine promoted osteogenesis and angiogenesis in zebrafish models by enhancing the expression of critical osteogenesis-associated genes, such as those coding for β-catenin and Runt-related transcription factor 2 (Runx2), and increasing the levels of the kinase insert domain receptor-like angiogenesis marker in aged zebrafish. In Parkinson’s disease models using patient-specific midbrain organoids with the leucine-rich repeat kinase 2 G2019S mutation, homotaurine treatment enhanced β-catenin expression and reduced ROS levels, highlighting its potential to counteract the oxidative stress and dysfunctional signaling pathways associated with neurodegeneration. Our findings suggest that homotaurine not only offers neuroprotective benefits but also holds promise as a dual-target therapeutic strategy for enhancing both neuronal and bone homeostasis in aging and neurodegenerative diseases. Full article
(This article belongs to the Special Issue Oxidative Stress in Age-Related Diseases)
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18 pages, 8094 KiB  
Article
Molecular Modulation of Threadfin Fish Brain to Hypoxia Challenge and Recovery Revealed by Multi-Omics Profiling
by Xiaoli Ma and Wen-Xiong Wang
Int. J. Mol. Sci. 2025, 26(4), 1703; https://doi.org/10.3390/ijms26041703 - 17 Feb 2025
Viewed by 195
Abstract
Migratory fish often encounter hypoxic zones during migration, which can lead to varying degrees of hypoxic stress. This issue has become increasingly severe due to human activities and climate change, which have resulted in the expansion of hypoxic zones in aquatic environments. However, [...] Read more.
Migratory fish often encounter hypoxic zones during migration, which can lead to varying degrees of hypoxic stress. This issue has become increasingly severe due to human activities and climate change, which have resulted in the expansion of hypoxic zones in aquatic environments. However, there is limited research on how these species respond to hypoxic stress and subsequent recovery. In this study, we used Eleutheronema tetradactylum, a well-recognized migratory and economically valuable fish species, as a model organism. Histological analysis revealed extensive neuronal damage during hypoxia exposure, with limited recovery observed even after 12 h of reoxygenation. Differential gene expression analysis highlighted progressive alterations in genes associated with stress response, neuroactive ligand interactions, and cellular repair mechanisms. Time-series analysis of differentially expressed genes (DEGs) identified critical expression profiles throughout the hypoxia-recovery process and revealed hub genes for each stage. Furthermore, dynamic changes in miRNA expression and proteomic profiles indicated active regulation of several key biological pathways, including MAPK, HIF-1, and ECM-receptor interactions. Through miRNA-mRNA-protein correlation analysis, we propose a model that predicts key regulatory pathways and critical miRNA-mRNA-protein interactions across the various stages of hypoxia-recovery in the brain of E. tetradactylum. This study presents the first integrated analysis of miRNA, mRNA, and protein throughout the entire hypoxia-recovery process in fish brains. The molecular interactions and regulatory pathways identified in this model could serve as valuable biomarkers for future research on hypoxia-recovery mechanisms in fish. Full article
(This article belongs to the Special Issue Molecular Biology of Hypoxia)
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21 pages, 2704 KiB  
Article
Resveratrol Ameliorates Chronic Stress in Kennel Dogs and Mice by Regulating Gut Microbiome and Metabolome Related to Tryptophan Metabolism
by Zhaowei Bian, Ziyang Li, Hao Chang, Jun Luo, Shiyan Jian, Jie Zhang, Peixin Lin, Baichuan Deng, Jinping Deng and Lingna Zhang
Antioxidants 2025, 14(2), 195; https://doi.org/10.3390/antiox14020195 - 9 Feb 2025
Viewed by 569
Abstract
Chronic stress poses threats to the physical and psychological well-being of dogs. Resveratrol (Res) is a polyphenol with antidepressant properties and has rarely been studied in dogs. This study aimed to investigate the stress-relieving effects and underlying mechanism of Res in dogs. Dogs [...] Read more.
Chronic stress poses threats to the physical and psychological well-being of dogs. Resveratrol (Res) is a polyphenol with antidepressant properties and has rarely been studied in dogs. This study aimed to investigate the stress-relieving effects and underlying mechanism of Res in dogs. Dogs were fed a basal diet supplemented with Res for 35 days. The fecal microbiota of the dogs was cultured with Res in vitro. The results show that Res improved the stress-related behaviors and increased the serum levels of 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF), immunoglobulin A, and antioxidant capacity in dogs. Res downregulated the hormones of the hypothalamic–pituitary–adrenal axis. The abundance of butyric-producing bacteria, like Blautia, increased, while the growth of Fusobacterium related to gut inflammation was inhibited in the Res group. A higher content of fecal butyric acid was observed in the Res group. The metabolome indicated that Res increased the fecal and serum levels of tryptophan (Trp) and decreased the consumption of Trp by microorganisms. A chronic unpredictable mild stress mouse model was established, and Res was administered for 35 days. The results show that Res ameliorated the stress-related behavior and increased the levels of Trp and 5-HT in the whole brains of mice. The relative mRNA expression of genes associated with the tight junction protein, aryl hydrocarbon receptor, and Trp transporters in the colon were upregulated. In conclusion, Res could ameliorate canine stress by increasing 5-HT, BDNF, and the antioxidant capacity and improving the immune function and stress response, which was attributed to the role of Res in the restructuring of gut microbiota and the modulation of tryptophan metabolism. Full article
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38 pages, 9543 KiB  
Article
Biotin Induces Inactive Chromosome X Reactivation and Corrects Physiopathological Alterations in Beta-Propeller-Protein-Associated Neurodegeneration
by Diana Reche-López, Ana Romero-González, Mónica Álvarez-Córdoba, Alejandra Suárez-Carrillo, Paula Cilleros-Holgado, Rocío Piñero-Pérez, David Gómez-Fernández, José Manuel Romero-Domínguez, Alejandra López-Cabrera, Susana González-Granero, José Manuel García-Verdugo and José A. Sánchez-Alcázar
Int. J. Mol. Sci. 2025, 26(3), 1315; https://doi.org/10.3390/ijms26031315 - 4 Feb 2025
Viewed by 504
Abstract
Neurodegeneration with brain iron accumulation (NBIA) involves a group of rare neurogenetic disorders often linked with iron overload in the basal nuclei of the brain presenting with spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration. Among NBIA subtypes, beta-propeller-protein-associated neurodegeneration (BPAN) is [...] Read more.
Neurodegeneration with brain iron accumulation (NBIA) involves a group of rare neurogenetic disorders often linked with iron overload in the basal nuclei of the brain presenting with spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration. Among NBIA subtypes, beta-propeller-protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45 (WD repeat domain 45). Previously, we demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism, and cell bioenergetics. In addition, antioxidant supplementation partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected. In this work, we explored the possibility of expressing the normal WDR45 allele present in the inactive chromosome X (Xi) of BPAN cells through treatment with epigenetic modulators. The aim of this study was to demonstrate whether biotin, an epigenetic nutrient, was able to restore the expression levels of WDR45 by a mechanism involving Xi reactivation and, consequently, correct BPAN defects. Our study demonstrated that biotin supplementation increases histone biotinylation and allows for the transcription of the WDR45 allele in Xi. Consequently, all physiopathological alterations in BPAN cells were notably corrected. The reactivation of Xi by epigenetic modulators can be a promising approach for the treatment of BPAN and other X-linked diseases. Full article
(This article belongs to the Special Issue Rare Diseases and Neuroscience)
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11 pages, 2399 KiB  
Article
Aging Reduces ATP-Binding Cassette Transporter Expression in Brain Microvessels of Mice
by Yukiyo Wada, Masaki Inoko, Kanako Ishihara, Karin Fukumoto, Yuya Tsurudome, Michiko Horiguchi, Akio Fujimura and Kentaro Ushijima
Pharmaceuticals 2025, 18(2), 191; https://doi.org/10.3390/ph18020191 - 30 Jan 2025
Viewed by 526
Abstract
Background: ATP-binding cassette (ABC) transporters are expressed in the vascular walls of brain capillaries and remove toxic chemicals from the brain. The expression of ABC transporters in peripheral organs is transcriptionally regulated by clock genes and exhibits 24 h periodic fluctuations. In addition, [...] Read more.
Background: ATP-binding cassette (ABC) transporters are expressed in the vascular walls of brain capillaries and remove toxic chemicals from the brain. The expression of ABC transporters in peripheral organs is transcriptionally regulated by clock genes and exhibits 24 h periodic fluctuations. In addition, clock gene outputs diminish with aging. In this study, we evaluated whether the expression of ABC transporters in the blood–brain barrier (BBB) of young mice had a 24 h cycle, and whether the expression of ABC transporters in the BBB decreased with age. Methods: Brain microvascular (BMV) fractions from the cerebral cortex of male C57BL/6J mice were prepared using dextran. BMV fractions from young mice (12 weeks old) were prepared every four hours to evaluate 24 h rhythmicity. BMV fractions from both young and aged mice (85 weeks old) were prepared when protein expression peaked (Zeitgeber Time 5). Protein and mRNA expression of ABC transporters in BMV fractions were measured. Results: In young mice, protein expression of P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein 4 showed time-dependent variations with a peak in the light phase (Zeitgeber Time 5); mRNA expression showed no time-dependent variation. The protein expression of these transporters was lower in the BBB of aged mice than in that of young mice, although mRNA expression did not differ between young and aged mice. Conclusions: ABC transporter protein expression levels in BMV endothelial cells decreased with aging; however, mRNA levels did not change, which suggests changes in protein expression did not result from diminished clock gene output. Further studies are needed to elucidate the mechanisms by which ABC transporter expression in the BBB decreases with aging. Full article
(This article belongs to the Section Pharmacology)
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15 pages, 2687 KiB  
Review
Is DEXI a Multiple Sclerosis Susceptibility Gene?
by Anna M. Eriksson, Nora Emini, Hanne F. Harbo and Tone Berge
Int. J. Mol. Sci. 2025, 26(3), 1175; https://doi.org/10.3390/ijms26031175 - 29 Jan 2025
Viewed by 411
Abstract
The genetic landscape of multiple sclerosis (MS) has been extensively mapped, yielding significant insights into the molecular mechanisms of the disorder. Early studies highlighted key genes associated with the immune system, particularly T cells, as critical for MS susceptibility. Subsequent large-scale genome-wide association [...] Read more.
The genetic landscape of multiple sclerosis (MS) has been extensively mapped, yielding significant insights into the molecular mechanisms of the disorder. Early studies highlighted key genes associated with the immune system, particularly T cells, as critical for MS susceptibility. Subsequent large-scale genome-wide association studies (GWASs) identified over 200 genetic variants linked to MS, revealing a complex interplay between MS risk and genes involved in various processes within adaptive and innate immune cells, as well as brain-resident microglia. Recently, a groundbreaking GWAS pinpointed the first gene variant associated with MS disease progression, distinguishing the mechanisms driving disease onset from those influencing progression. The C-type lectin domain family 16, member A (CLEC16A) gene within the 16p13 region has consistently been shown to be associated with increased risk of developing both MS and other autoimmune disorders. Notably, several autoimmune-associated genetic variants in CLEC16A introns act as expression quantitative trait loci for the dexamethasone-induced protein (DEXI gene, adding DEXI to the growing list of MS susceptibility genes. This review explores the molecular and functional characterization of DEXI with a particular focus on recent advances in understanding its role in autoimmunity, specifically in the context of multiple sclerosis. We underscore the importance of continued molecular investigation of susceptibility loci for MS identified in genetic studies, with the goal of translating this knowledge into clinical applications. Full article
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11 pages, 817 KiB  
Article
Sevoflurane Preconditioning Rescues PKMζ Gene Expression from Broad Hypoxia-Induced mRNA Downregulation Correlating with Improved Neuronal Recovery
by Joan Y. Hou, Kim D. Allen, A. Iván Hernandez, James E. Cottrell and Ira S. Kass
NeuroSci 2025, 6(1), 9; https://doi.org/10.3390/neurosci6010009 - 28 Jan 2025
Viewed by 925
Abstract
Hypoxia due to stroke is a major cause of neuronal damage, leading to loss of cognition and other brain functions. Sevoflurane preconditioning improves recovery after hypoxia. Hypoxia interferes with protein expression at the translational level; however, its effect on mRNA levels for neuronal [...] Read more.
Hypoxia due to stroke is a major cause of neuronal damage, leading to loss of cognition and other brain functions. Sevoflurane preconditioning improves recovery after hypoxia. Hypoxia interferes with protein expression at the translational level; however, its effect on mRNA levels for neuronal protein kinase and anti-apoptotic genes is unclear. To investigate the link between sevoflurane preconditioning and gene expression, hippocampal slices were treated with 4% sevoflurane for 15 min, a 5 min washout, 10 min of hypoxia, and 60 min of recovery. We used quantitative PCR to measure mRNA levels in the CA1 region of rat hippocampi. The mRNA levels for specific critical proteins were examined, as follows: Protein kinases, PKCγ (0.22), PKCε (0.38), and PKMζ (0.55) mRNAs, and anti-apoptotic, bcl-2 (0.44) and bcl-xl (0.41), were reduced 60 min after hypoxia relative to their expression in tissue not subjected to hypoxia (set to 1.0). Sevoflurane preconditioning prevented the reduction in PKMζ (0.88 vs. 1.0) mRNA levels after hypoxia. Pro-apoptotic BAD mRNA was not significantly changed after hypoxia, even with sevoflurane preconditioning (hypoxia 0.81, sevo hypoxia 0.84 vs. normoxia 1.0). However, BAD mRNA was increased by sevoflurane in non-hypoxic conditions (1.48 vs. 1.0), which may partially explain the deleterious effects of volatile anesthetics under certain conditions. The DNA repair enzyme poly ADP-ribose polymerase 1 (PARP-1) was increased by sevoflurane in tissue not subjected to hypoxia (1.23). PARP-1 mRNA was reduced in untreated tissue after hypoxia (0.21 vs. 1.0); sevoflurane did not improve PARP-1 after hypoxia (0.27). Interestingly, the mRNA level of the cognitive kinase PKMζ, a kinase essential for learning and memory, was the only one protected against hypoxic downregulation by sevoflurane preconditioning. These findings correlate with previous studies that found that sevoflurane-induced improvement of neuronal survival after hypoxia was dependent on PKMζ. Maintaining mRNA levels for critical proteins may provide an important mechanism for preserving neuronal function after stroke. Full article
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17 pages, 4727 KiB  
Article
The Antidepressant Effect of Resveratrol Is Related to Neuroplasticity Mediated by the ELAVL4-Bdnf mRNA Pathway
by Hailong Ge, Lujia Si, Chen Li, Junjie Huang, Limin Sun, Lan Wu, Yinping Xie, Ling Xiao and Gaohua Wang
Int. J. Mol. Sci. 2025, 26(3), 1113; https://doi.org/10.3390/ijms26031113 - 27 Jan 2025
Viewed by 724
Abstract
Resveratrol, a plant-derived polyphenol, exhibits significant antidepressant effects and notably enhances neuroplasticity in neurological diseases. However, whether the antidepressant function of resveratrol is related to neuroplasticity remains uncertain, and the underlying mechanisms is poorly understood. This study aims to investigate the role and [...] Read more.
Resveratrol, a plant-derived polyphenol, exhibits significant antidepressant effects and notably enhances neuroplasticity in neurological diseases. However, whether the antidepressant function of resveratrol is related to neuroplasticity remains uncertain, and the underlying mechanisms is poorly understood. This study aims to investigate the role and mechanism of resveratrol in neuroplasticity in depression. Here, we adopted the chronic unpredictable mild stress (CUMS) model and resveratrol intervention by oral gavage. Thereafter, behavioral tests confirmed resveratrol’s antidepressant effect, and Nissl staining, Golgi staining, and Western blotting (WB) were employed to assess the neuronal plasticity. Moreover, proteomic analysis and WB were used to screen and identify the key proteins. To investigate the downstream target of ELAV-like RNA-binding protein 4 (ELAVL4) (one of candidate genes), the RNA Interactome Database and the National Center for Biotechnology Information databases were utilized to predict the targets of ELAVL4. Finally, Quantitative PCR, WB, and Immunofluorescence were used to verify the prediction. Our results indicate that resveratrol alleviates CUMS-induced depressive-like behaviors accompanied by the restoration of impaired hippocampal neuroplasticity. Then, proteomic analysis shows that 351 differentially expressed proteins (DEPs) decrease after CUMS, while 24 DEPs increase remarkably with the resveratrol treatment. Among which, ELAVL4 is downregulated by CUMS, simultaneously increasing after resveratrol intervention, which acts as a protective protein in this process. Finally, brain-derived neurotrophic factor (Bdnf) mRNA is predicted to be the potential target of ELAVL4 and validated by molecular technologies. In conclusion, our findings demonstrate that resveratrol’s antidepressant efficacy is closely associated with ELAVL4, an RNA-binding protein, a mediated neuroplasticity pathway, potentially intersecting with the Bdnf mRNA. Overall, this research sheds light on the role of the ELAVL4-Bdnf mRNA pathway through neuroplasticity in resveratrol’s antidepressant action, which provides an mRNA regulation perspective for the development of novel antidepressants and understanding depression pathology. Full article
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20 pages, 7231 KiB  
Article
Genome-Wide Identification, Characterization of the ORA (Olfactory Receptor Class A) Gene Family, and Potential Roles in Bile Acid and Pheromone Recognition in Mandarin Fish (Siniperca chuatsi)
by Xiaoru Dong, Maolin Lv, Ming Zeng, Xiaochuan Chen, Jiale Wang and Xu-Fang Liang
Cells 2025, 14(3), 189; https://doi.org/10.3390/cells14030189 - 26 Jan 2025
Viewed by 816
Abstract
The ORA (olfactory receptor class A) gene family in teleosts is related to the V1R (vomeronasal 1 receptors) family in mammals and plays a key role in odor detection. Although ORA genes have been identified in several teleosts, their characteristics in mandarin fish [...] Read more.
The ORA (olfactory receptor class A) gene family in teleosts is related to the V1R (vomeronasal 1 receptors) family in mammals and plays a key role in odor detection. Although ORA genes have been identified in several teleosts, their characteristics in mandarin fish (Siniperca chuatsi) have not been explored. In this study, we conducted a comprehensive genomic analysis of the mandarin fish and discovered a complete ORA gene family consisting of five members located on chromosome 2 (ORA1, ORA2, ORA3, ORA4) and chromosome 16 (ORA6). Phylogenetic, synteny, and gene structure analyses revealed typical exon–intron conservation with strong evidence of purifying selection. Tissue expression analysis showed distinct expression profiles for each ORA gene, with some showing sexual dimorphism in specific tissues. The expression of ORA1 and ORA2 in the olfactory epithelium exhibits sexual dimorphism, while ORA3 shows sexual dimorphism in the brain. In situ hybridization confirmed that ORA1, ORA2, ORA3, and ORA6 are expressed in the microvillar sensory neurons of the olfactory epithelium, while ORA4 is expressed in crypt cells. Additionally, molecular docking simulations indicated that the five ORA proteins have a high binding affinity with seven bile acids (LAC, GLAC, CA, TLCA, 3-KLCA, 7-KLCA, and 12-KLCA), with ORAs showing stronger binding affinity with LCA and CA. This study comprehensively characterizes the ORA gene family in mandarin fish, examining its phylogeny, synteny, gene structure, and selection pressure. Furthermore, we found that each ORA displays a distinct expression pattern across multiple tissues, with notable sexual dimorphism, and shows potential binding interactions with specific bile acids and pheromones. Our findings provide valuable insights that enhance the overall understanding of fish ORAs and their potential functions. Full article
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10 pages, 245 KiB  
Article
Elucidating the Interplay of Hypoxia-Inducible Factor and Circadian Clock Signaling in Obstructive Sleep Apnea Patients
by Agata Gabryelska, Szymon Turkiewicz, Adrian Gajewski, Piotr Białasiewicz, Dominik Strzelecki, Marta Ditmer, Maciej Chałubiński and Marcin Sochal
Int. J. Mol. Sci. 2025, 26(3), 971; https://doi.org/10.3390/ijms26030971 - 24 Jan 2025
Viewed by 516
Abstract
Background: Hypoxia-inducible factor 1 (HIF-1) affects the circadian clock in obstructive sleep apnea (OSA) and may have a bidirectional relationship with circadian mechanisms. This study examined the link between circadian clock and HIF-1 in OSA patients versus controls. Methods: 70 participants underwent polysomnography [...] Read more.
Background: Hypoxia-inducible factor 1 (HIF-1) affects the circadian clock in obstructive sleep apnea (OSA) and may have a bidirectional relationship with circadian mechanisms. This study examined the link between circadian clock and HIF-1 in OSA patients versus controls. Methods: 70 participants underwent polysomnography (PSG), and were assigned into OSA (apnea–hypopnea index (AHI) ≥ 5, n = 54) or control (AHI < 5, n = 16) groups. BMAL1 (brain and muscle ARNT like 1), CLOCK (circadian locomotor output cycles kaput), PER1 (period 1), CRY1 (cryptochrome 1), HIF-1α, and HIF-1β gene expressions and protein levels were measured in evening and morning samples, collected before and after PSG. Results: The OSA group was characterized by increased CLOCK, CRY1, PER1 and HIF-1a protein levels, both in the morning and evening (all p < 0.05), and decreased morning expression of BMAL1 (p = 0.02). Associations between almost all circadian clock gene expressions and both HIF-1 subunits were observed in the OSA group at both time points (all p < 0.05), apart from association between PER1 and HIF-1α in the morning (R = 0.050, p = 0.73). In controls, only a correlation between HIF-1α levels and CRY1 expression in the morning (R = 0.588, p = 0.02) was found. Conclusions: OSA affects the circadian clock and HIF-1 pathway, with increased CLOCK, CRY1, PER1, and HIF-1α protein levels observed in OSA patients. The interplay between these systems may involve complex posttranscriptional and posttranslational mechanisms. Full article
(This article belongs to the Section Molecular Biology)
14 pages, 3034 KiB  
Article
HERC1 E3 Ubiquitin Ligase Is Necessary for Autophagy Processes and for the Maintenance and Homeostasis of Vesicles in Motor Nerve Terminals, but Not for Proteasomal Activity
by Miguel Ángel Pérez-Castro, Francisco Hernández-Rasco, Isabel María Alonso-Bellido, María S. Letrán-Sánchez, Eva María Pérez-Villegas, Joana Vitallé, Luis Miguel Real, Ezequiel Ruiz-Mateos, José Luis Venero, Lucía Tabares, Ángel Manuel Carrión, José Ángel Armengol, Sara Bachiller and Rocío Ruiz
Int. J. Mol. Sci. 2025, 26(2), 793; https://doi.org/10.3390/ijms26020793 - 18 Jan 2025
Viewed by 639
Abstract
The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection [...] Read more.
The ubiquitin proteasome system (UPS) is implicated in protein homeostasis. One of the proteins involved in this system is HERC1 E3 ubiquitin ligase, which was associated with several processes including the normal development and neurotransmission at the neuromuscular junction (NMJ), autophagy in projection neurons, myelination of the peripheral nervous system, among others. The tambaleante (tbl) mouse model carries the spontaneous mutation Gly483Glu substitution in the HERC1 E3 protein. Using this model, we analyzed the implication of HERC1 E3 ubiquitin ligase in the activity of UPS, autophagy, and synaptic homeostasis in brain and muscle tissues. Regarding UPS, no differences were found in its activity nor in the specific gene expression in both brain and muscle tissues from tbl compared with the control littermates. Furthermore, the use of the specific UPS inhibitor (MG-132), did not alter the evoked neurotransmitter release in the levator auris longus (LAL) muscle. Interestingly, the expression of the autophagy-related gene p62 was significantly increased in the muscle of tbl compared to the control littermates. Indeed, impaired evoked neurotransmitter release was observed with the autophagy inhibitor Wortmannin. Finally, altered levels of Clathrin and Synaptophysin were detected in muscle tissues. Altogether, our findings show that HERC1 E3 ubiquitin ligase mutation found in tbl mice alters autophagy and vesicular recycling without affecting proteasomal function. Full article
(This article belongs to the Special Issue Molecular and Neuromuscular Mechanisms in Skeletal Muscle Aging)
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21 pages, 6707 KiB  
Article
Derivation and Characterization of Isogenic OPA1 Mutant and Control Human Pluripotent Stem Cell Lines
by Katherine A. Pohl, Xiangmei Zhang, Johnny Jeonghyun Ji, Linsey Stiles, Alfredo A. Sadun and Xian-Jie Yang
Cells 2025, 14(2), 137; https://doi.org/10.3390/cells14020137 - 17 Jan 2025
Viewed by 811
Abstract
Dominant optic atrophy (DOA) is the most commonly inherited optic neuropathy. The majority of DOA is caused by mutations in the OPA1 gene, which encodes a dynamin-related GTPase located to the mitochondrion. OPA1 has been shown to regulate mitochondrial dynamics and promote fusion. [...] Read more.
Dominant optic atrophy (DOA) is the most commonly inherited optic neuropathy. The majority of DOA is caused by mutations in the OPA1 gene, which encodes a dynamin-related GTPase located to the mitochondrion. OPA1 has been shown to regulate mitochondrial dynamics and promote fusion. Within the mitochondrion, proteolytically processed OPA1 proteins form complexes to maintain membrane integrity and the respiratory chain complexity. Although OPA1 is broadly expressed, human OPA1 mutations predominantly affect retinal ganglion cells (RGCs) that are responsible for transmitting visual information from the retina to the brain. Due to the scarcity of human RGCs, DOA has not been studied in depth using the disease affected neurons. To enable studies of DOA using stem-cell-derived human RGCs, we performed CRISPR-Cas9 gene editing to generate OPA1 mutant pluripotent stem cell (PSC) lines with corresponding isogenic controls. CRISPR-Cas9 gene editing yielded both OPA1 homozygous and heterozygous mutant ESC lines from a parental control ESC line. In addition, CRISPR-mediated homology-directed repair (HDR) successfully corrected the OPA1 mutation in a DOA patient’s iPSCs. In comparison to the isogenic controls, the heterozygous mutant PSCs expressed the same OPA1 protein isoforms but at reduced levels; whereas the homozygous mutant PSCs showed a loss of OPA1 protein and altered mitochondrial morphology. Furthermore, OPA1 mutant PSCs exhibited reduced rates of oxygen consumption and ATP production associated with mitochondria. These isogenic PSC lines will be valuable tools for establishing OPA1-DOA disease models in vitro and developing treatments for mitochondrial deficiency associated neurodegeneration. Full article
(This article belongs to the Special Issue Mitochondria and Other Organelles in Neurodegenerative Diseases)
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14 pages, 1191 KiB  
Communication
Glycosylation Pathways Targeted by Deregulated miRNAs in Autism Spectrum Disorder
by Federica Mirabella, Martina Randazzo, Alessandro Rinaldi, Fabio Pettinato, Renata Rizzo, Luisa Sturiale and Rita Barone
Int. J. Mol. Sci. 2025, 26(2), 783; https://doi.org/10.3390/ijms26020783 - 17 Jan 2025
Viewed by 746
Abstract
Autism Spectrum Disorder (ASD) is a complex condition with a multifactorial aetiology including both genetic and epigenetic factors. MicroRNAs (miRNAs) play a role in ASD and may influence metabolic pathways. Glycosylation (the glycoconjugate synthesis pathway) is a necessary process for the optimal development [...] Read more.
Autism Spectrum Disorder (ASD) is a complex condition with a multifactorial aetiology including both genetic and epigenetic factors. MicroRNAs (miRNAs) play a role in ASD and may influence metabolic pathways. Glycosylation (the glycoconjugate synthesis pathway) is a necessary process for the optimal development of the central nervous system (CNS). Congenital Disorders of Glycosylation (CDGs) (CDGs) are linked to over 180 genes and are predominantly associated with neurodevelopmental disorders (NDDs) including ASD. From a literature search, we considered 64 miRNAs consistently deregulated in ASD patients (ASD-miRNAs). Computational tools, including DIANA-miRPath v3.0 and TarBase v8, were employed to investigate the potential involvement of ASD-miRNAs in glycosylation pathways. A regulatory network constructed through miRNet 2.0 revealed the involvement of these miRNAs in targeting genes linked to glycosylation. Protein functions were further validated through the Human Protein Atlas. A total of twenty-five ASD-miRNAs were identified, including nine miRNAs that were differentially expressed in cells or brain tissue in ASD patients and associated with glycosylation pathways, specifically protein N- and O-glycosylation and glycosaminoglycan biosynthesis (heparan sulfate). A number of CDG genes and/or ASD-risk genes, including DOLK, GALNT2, and EXT1, were identified as targets, along with validated interactions involving four key miRNAs (hsa-miR-423-5p, hsa-miR-30c-5p, hsa-miR-195-5p, and hsa-miR-132-5p). B4GALT1, an ASD susceptibility gene, emerged as a central regulatory hub, reinforcing the link between glycosylation and ASD. In sum, the evidence presented here supports the hypothesis that ASD-miRNAs mediate the epigenetic regulation of glycosylation, thus unveiling possible novel patho-mechanisms underlying ASD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation: 2nd Edition)
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26 pages, 4613 KiB  
Article
Decoding Codon Bias: The Role of tRNA Modifications in Tissue-Specific Translation
by Daisuke Ando, Sherif Rashad, Thomas J. Begley, Hidenori Endo, Masashi Aoki, Peter C. Dedon and Kuniyasu Niizuma
Int. J. Mol. Sci. 2025, 26(2), 706; https://doi.org/10.3390/ijms26020706 - 15 Jan 2025
Viewed by 1025
Abstract
The tRNA epitranscriptome has been recognized as an important player in mRNA translation regulation. Our knowledge of the role of the tRNA epitranscriptome in fine-tuning translation via codon decoding at tissue or cell levels remains incomplete. We analyzed tRNA expression and modifications as [...] Read more.
The tRNA epitranscriptome has been recognized as an important player in mRNA translation regulation. Our knowledge of the role of the tRNA epitranscriptome in fine-tuning translation via codon decoding at tissue or cell levels remains incomplete. We analyzed tRNA expression and modifications as well as codon optimality across seven mouse tissues. Our analysis revealed distinct enrichment patterns of tRNA modifications in different tissues. Queuosine (Q) tRNA modification was most enriched in the brain compared to other tissues, while mitochondrial tRNA modifications and tRNA expression were highest in the heart. Using this observation, we synthesized, and delivered in vivo, codon-mutated EGFP for Q-codons, where the C-ending Q-codons were replaced with U-ending codons. The protein levels of mutant EGFP were downregulated in liver, which is poor in Q, while in brain EGFP, levels did not change. These data show that understanding tRNA modification enrichments across tissues is not only essential for understanding codon decoding and bias but can also be utilized for optimizing gene and mRNA therapeutics to be more tissue-, cell-, or condition-specific. Full article
(This article belongs to the Special Issue Advanced Research of tRNA)
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25 pages, 11151 KiB  
Article
Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq
by Christophe Desterke, Yuanji Fu, Jenny Bonifacio-Mundaca, Claudia Monge, Pascal Pineau, Jorge Mata-Garrido and Raquel Francés
Antioxidants 2025, 14(1), 96; https://doi.org/10.3390/antiox14010096 - 15 Jan 2025
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Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can [...] Read more.
Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can be induced in medulloblastoma cells in vitro using erastin or RSL3. Using two independent medulloblastoma RNA-sequencing cohorts (MB-PBTA and MTAB-10767), we investigated the expression of ferroptosis-related molecules through multiple approaches, including Weighted Gene Co-Expression Network Analysis (WGCNA), molecular subtype stratification, protein–protein interaction (PPI) networks, and univariable and multivariable overall survival analyses. A prognostic expression score was computed based on a cross-validated ferroptosis signature. In training and validation cohorts, the regulation of the ferroptosis transcriptional program distinguished the four molecular subtypes of medulloblastoma. WGCNA identified nine gene modules in the MB tumor transcriptome; five correlated with molecular subtypes, implicating pathways related to oxidative stress, hypoxia, and trans-synaptic signaling. One module, associated with disease recurrence, included epigenetic regulators and nucleosome organizers. Univariable survival analyses identified a 45-gene ferroptosis prognostic signature associated with nutrient sensing, cysteine and methionine metabolism, and trans-sulfuration within a one-carbon metabolism. The top ten unfavorable ferroptosis genes included CCT3, SNX5, SQOR, G3BP1, CARS1, SLC39A14, FAM98A, FXR1, TFAP2C, and ATF4. Patients with a high ferroptosis score showed a worse prognosis, particularly in the G3 and SHH subtypes. The PPI network highlighted IL6 and CBS as unfavorable hub genes. In a multivariable overall survival model, which included gender, age, and the molecular subtype classification, the ferroptosis expression score was validated as an independent adverse prognostic marker (hazard ratio: 5.8; p-value = 1.04 × 10−9). This study demonstrates that the regulation of the ferroptosis transcriptional program is linked to medulloblastoma molecular subtypes and patient prognosis. A cross-validated ferroptosis signature was identified in two independent RNA-sequencing cohorts, and the ferroptosis score was confirmed as an independent and adverse prognostic factor in medulloblastoma. Full article
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