NeuroMolecular Medicine最新文献_第10页

Uncovering Sex-Specific Epigenetic Regulatory Mechanism Involving H3k9me2 in Neural Inflammation, Damage, and Recovery in the Internal Carotid Artery Occlusion Mouse Model. 揭示H3k9me2参与颈内动脉闭塞小鼠模型神经炎症、损伤和恢复的性别特异性表观遗传调控机制

IF 3.3 4区医学

NeuroMolecular Medicine Pub Date : 2024-02-26 DOI: 10.1007/s12017-023-08768-9

Mydhili Radhakrishnan, Vincy Vijay, B Supraja Acharya, Papia Basuthakur, Shashikant Patel, Kalyani Soren, Arvind Kumar, Sumana Chakravarty

{"title":"Uncovering Sex-Specific Epigenetic Regulatory Mechanism Involving H3k9me2 in Neural Inflammation, Damage, and Recovery in the Internal Carotid Artery Occlusion Mouse Model.","authors":"Mydhili Radhakrishnan, Vincy Vijay, B Supraja Acharya, Papia Basuthakur, Shashikant Patel, Kalyani Soren, Arvind Kumar, Sumana Chakravarty","doi":"10.1007/s12017-023-08768-9","DOIUrl":"10.1007/s12017-023-08768-9","url":null,"abstract":"Cerebral ischemic stroke is one of the foremost global causes of death and disability. Due to inadequate knowledge in its sequential disease mechanisms, therapeutic efforts to mitigate acute ischemia-induced brain injury are limited. Recent studies have implicated epigenetic mechanisms, mostly histone lysine acetylation/deacetylation, in ischemia-induced neural damage and death. However, the role of lysine methylation/demethylation, another prevalent epigenetic mechanism in cerebral ischemia has not undergone comprehensive investigation, except a few recent reports, including those from our research cohort. Considering the impact of sex on post-stroke outcomes, we studied both male and female mice to elucidate molecular details using our recently developed Internal Carotid Artery Occlusion (ICAO) model, which induces mild to moderate cerebral ischemia, primarily affecting the striatum and ventral hippocampus. Here, we demonstrate for the first time that female mice exhibit faster recovery than male mice following ICAO, evaluated through neurological deficit score and motor coordination assessment. Furthermore, our investigation unveiled that dysregulated histone lysine demethylases (KDMs), particularly kdm4b/jmjd2b are responsible for the sex-specific variance in the modulation of inflammatory genes. Building upon our prior reportage blocking KDMs by DMOG (Dimethyloxalylglycine) and thus preventing the attenuation in H3k9me2 reduced the post-ICAO transcript levels of the inflammatory molecules and neural damage, our present study delved into investigating the differential role of H3k9me2 in the regulation of pro-inflammatory genes in female vis-à-vis male mice underlying ICAO-induced neural damage and recovery. Overall, our results reveal the important role of epigenetic mark H3k9me2 in mediating sex-specific sequential events in inflammatory response, elicited post-ICAO.","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"26 1","pages":"3"},"PeriodicalIF":3.3,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139972774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of Chronic Hypertension on the Energy Metabolism of Cerebral Cortex Mitochondria in Normotensive and in Spontaneously Hypertensive Rats During Aging. 慢性高血压对正常血压和自发性高血压大鼠衰老过程中大脑皮层线粒体能量代谢的影响

IF 3.3 4区医学

NeuroMolecular Medicine Pub Date : 2024-02-23 DOI: 10.1007/s12017-023-08772-z

Roberto Federico Villa, Federica Ferrari, Antonella Gorini

{"title":"Effects of Chronic Hypertension on the Energy Metabolism of Cerebral Cortex Mitochondria in Normotensive and in Spontaneously Hypertensive Rats During Aging.","authors":"Roberto Federico Villa, Federica Ferrari, Antonella Gorini","doi":"10.1007/s12017-023-08772-z","DOIUrl":"10.1007/s12017-023-08772-z","url":null,"abstract":"In this study the subcellular modifications undergone by cerebral cortex mitochondrial metabolism in chronic hypertension during aging were evaluated. The catalytic properties of regulatory energy-linked enzymes of Tricarboxylic Acid Cycle (TCA), Electron Transport Chain (ETC) and glutamate metabolism were assayed on non-synaptic mitochondria (FM, located in post-synaptic compartment) and on intra-synaptic mitochondria of pre-synaptic compartment, furtherly divided in \"light\" (LM) and \"heavy\" (HM) mitochondria, purified form cerebral cortex of normotensive Wistar Kyoto Rats (WKY) versus Spontaneously Hypertensive Rats (SHR) at 6, 12 and 18 months. During physiological aging, the metabolic machinery was differently expressed in pre- and post-synaptic compartments: LM and above all HM were more affected by aging, displaying lower ETC activities. In SHR at 6 months, FM and LM showed an uncoupling between TCA and ETC, likely as initial adaptive response to hypertension. During pathological aging, HM were particularly affected at 12 months in SHR, as if the adaptive modifications in FM and LM at 6 months granted a mitochondrial functional balance, while at 18 months all the neuronal mitochondria displayed decreased metabolic fluxes versus WKY. This study describes the effects of chronic hypertension on cerebral mitochondrial energy metabolism during aging through functional proteomics of enzymes at subcellular levels, i.e. in neuronal soma and synapses. In addition, this represents the starting point to envisage an experimental physiopathological model which could be useful also for pharmacological studies, to assess drug actions during the development of age-related pathologies that could coexist and/or are provoked by chronic hypertension.","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"26 1","pages":"2"},"PeriodicalIF":3.3,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Amelioration of Astrocyte-Mediated Neuroinflammation by EI-16004 Confers Neuroprotection in an MPTP-induced Parkinson's Disease Model. EI-16004能改善星形胶质细胞介导的神经炎症，从而在MPTP诱导的帕金森病模型中提供神经保护。

IF 3.3 4区医学

NeuroMolecular Medicine Pub Date : 2024-01-30 DOI: 10.1007/s12017-023-08769-8

Jaehoon Kim, Seulah Lee, Dong Geun Hong, Seonguk Yang, Cong So Tran, Jinsook Kwak, Min-Ju Kim, Thenmozhi Rajarathinam, Ki Wung Chung, Young-Suk Jung, Akihito Ishigami, Seung-Cheol Chang, Haeseung Lee, Hwayoung Yun, Jaewon Lee

{"title":"Amelioration of Astrocyte-Mediated Neuroinflammation by EI-16004 Confers Neuroprotection in an MPTP-induced Parkinson's Disease Model.","authors":"Jaehoon Kim, Seulah Lee, Dong Geun Hong, Seonguk Yang, Cong So Tran, Jinsook Kwak, Min-Ju Kim, Thenmozhi Rajarathinam, Ki Wung Chung, Young-Suk Jung, Akihito Ishigami, Seung-Cheol Chang, Haeseung Lee, Hwayoung Yun, Jaewon Lee","doi":"10.1007/s12017-023-08769-8","DOIUrl":"10.1007/s12017-023-08769-8","url":null,"abstract":"Parkinson's disease (PD) is a neurodegenerative disorder that results in motor impairment due to dopaminergic neuronal loss. The pathology of PD is closely associated with neuroinflammation, which can be characterized by astrocyte activation. Thus, targeting the inflammatory response in astrocytes might provide a novel therapeutic approach. We conducted a luciferase assay on an in-house chemical library to identify compounds with anti-inflammatory effects capable of reducing MPP+-induced NF-κB activity in astrocytes. Among the compounds identified, EI-16004, a novel 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides, exhibited a significant anti-inflammatory effect by significantly reducing MPP+-induced astrocyte activation. Biochemical analysis and docking simulation indicated that EI-16004 inhibited the MPP+-induced phosphorylation of p65 by attenuating ERK phosphorylation, and EI-16004 reduced pro-inflammatory cytokine and chemokine levels in astrocytes. In vivo studies on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in male C57BL/6 mice showed that EI-16004 ameliorated motor impairment and protected against dopaminergic neuronal loss, and EI-16004 effectively mitigated the MPTP-induced astrocyte activation in striatum (STR) and substantia nigra (SN). These results indicate EI-16004 is a potential neuroprotective agent for the prevention and treatment of astrocyte-mediated neuroinflammatory conditions in PD.","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":"26 1","pages":"1"},"PeriodicalIF":3.3,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Author Correction: Potential of Quercetin to Protect Cadmium Induced Cognitive Deficits in Rats by Modulating NMDA‑R Mediated Downstream Signaling and PI3K/AKT-Nrf2/ARE Signaling Pathways in Hippocampus. 作者更正：槲皮素通过调节海马NMDA‑R介导的下游信号传导和PI3K/AKT-Nrf2/ARE信号传导途径保护镉诱导的大鼠认知缺陷的潜力。

IF 3.5 4区医学

NeuroMolecular Medicine Pub Date : 2023-12-01 DOI: 10.1007/s12017-023-08765-y

Anugya Srivastava, Anima Kumari, Pankaj Jagdale, Anjaneya Ayanur, Aditya Bhushan Pant, Vinay Kumar Khanna

引用次数: 0

Diurnal Characteristics of the Orexin System Genes and Its Effects on Pathology at Early Stage in 3xTg-AD Mice. Orexin系统基因在3xTg-AD小鼠早期的昼夜特性及其对病理学的影响。

IF 3.5 4区医学

NeuroMolecular Medicine Pub Date : 2023-12-01 Epub Date: 2023-10-16 DOI: 10.1007/s12017-023-08767-w

Jing Yin, Chun-Mei Tuo, Kai-Yue Yu, Xiao-Hong Hu, Yan-Ying Fan, Mei-Na Wu

{"title":"Diurnal Characteristics of the Orexin System Genes and Its Effects on Pathology at Early Stage in 3xTg-AD Mice.","authors":"Jing Yin, Chun-Mei Tuo, Kai-Yue Yu, Xiao-Hong Hu, Yan-Ying Fan, Mei-Na Wu","doi":"10.1007/s12017-023-08767-w","DOIUrl":"10.1007/s12017-023-08767-w","url":null,"abstract":"Orexin and its receptors are closely related to the pathogenesis of Alzheimer's disease (AD). Although the expression of orexin system genes under physiological condition has circadian rhythm, the diurnal characteristics of orexin system genes, and its potential role in the pathogenesis in AD are unknown. In the present study, we hope to elucidate the diurnal characteristics of orexin system genes at the early stage of AD, and to investigate its potential role in the development of AD neuropathology. We firstly detected the mRNA levels of orexin system genes, AD risk genes and core clock genes (CCGs) in hypothalamus and hippocampus in 6-month-old male 3xTg-AD mice and C57BL/6J (wild type, WT) control mice, then analyzed diurnal expression profiles of all genes using JTK_CYCLE algorithm, and did the correlation analysis between expression of orexin system genes and AD risk genes or CCGs. In addition, the expression of β-amyloid protein (Aβ) and phosphorylated tau (p-tau) protein were measured. The results showed that the diurnal mRNA expression profiles of PPO, OX1R, OX2R, Bace2, Bmal1, Per1, Per2 and Cry1 in the hypothalamus, and gene expression of OX1R, OX2R, Bace1, Bmal1, Per1 and Cry2 in the hippocampus in 3xTg-AD mice were different from that in WT mice. Furthermore, there is positive correlation between orexin system genes and AD risk genes or CCGs in the brain in 3xTg-AD mice. In addition, the expression of Aβ and p-tau in hippocampus in 3xTg-AD mice were significantly increased, and the expression of p-tau is higher in night than in day. These results indicate that the abnormal expression profiles of orexin system genes and its interaction with AD risk genes or CCGs might exert important role in the pathogenesis of AD, which will increase the expression of Aβ and p-tau, and accelerate the development of AD.","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":" ","pages":"632-643"},"PeriodicalIF":3.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Role of Ubiquitin-Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease. 泛素-蛋白酶体系统和丝裂噬在帕金森病发病机制中的作用

IF 3.5 4区医学

NeuroMolecular Medicine Pub Date : 2023-12-01 Epub Date: 2023-09-12 DOI: 10.1007/s12017-023-08755-0

Yu Liang, Guangshang Zhong, Mingxin Ren, Tingting Sun, Yangyang Li, Ming Ye, Caiyun Ma, Yu Guo, Changqing Liu

{"title":"The Role of Ubiquitin-Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease.","authors":"Yu Liang, Guangshang Zhong, Mingxin Ren, Tingting Sun, Yangyang Li, Ming Ye, Caiyun Ma, Yu Guo, Changqing Liu","doi":"10.1007/s12017-023-08755-0","DOIUrl":"10.1007/s12017-023-08755-0","url":null,"abstract":"Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and diverse. The ubiquitin-proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. Dysfunction of components and substrates of this UPS has been linked to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Moreover, UPS can regulate α-synuclein misfolding and aggregation, mitophagy, neuroinflammation and oxidative stress to affect the development of PD. In the present study, we review the role of several related E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) on the pathogenesis of PD such as Parkin, CHIP, USP8, etc. On this basis, we summarize the connections and differences of different E3 ubiquitin ligases in the pathogenesis, and elaborate on the regulatory progress of different DUBs on the pathogenesis of PD. Therefore, we can better understand their relationships and provide feasible and valuable therapeutic clues for UPS-related PD treatment research.","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":" ","pages":"471-488"},"PeriodicalIF":3.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10211710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Increased IL-6 Levels and the Upregulation of Iron Regulatory Biomarkers Contribute to the Progression of Japanese Encephalitis Virus Infection's Pathogenesis. IL-6水平升高和铁调节生物标志物的上调有助于日本脑炎病毒感染发病机制的进展。

IF 3.5 4区医学

NeuroMolecular Medicine Pub Date : 2023-12-01 Epub Date: 2023-10-31 DOI: 10.1007/s12017-023-08762-1

Anjali Singh, Sneha Ghildiyal, Prabhaker Mishra, Gajendra Singh, Himanshu Dandu, Alok Kumar

{"title":"Increased IL-6 Levels and the Upregulation of Iron Regulatory Biomarkers Contribute to the Progression of Japanese Encephalitis Virus Infection's Pathogenesis.","authors":"Anjali Singh, Sneha Ghildiyal, Prabhaker Mishra, Gajendra Singh, Himanshu Dandu, Alok Kumar","doi":"10.1007/s12017-023-08762-1","DOIUrl":"10.1007/s12017-023-08762-1","url":null,"abstract":"Integrated analysis of iron regulatory biomarkers and inflammatory response could be an important strategy for Japanese encephalitis viral (JEV) infection disease management. In the present study, the inflammatory response was assessed by measuring serum Interleukin-6 (IL-6) levels using ELISA, and the transcription levels of iron homeostasis regulators were analyzed via RT-PCR. Furthermore, inter-individual variation in the transferrin gene was analyzed by PCR-RFLP and their association with clinical symptoms, susceptibility, severity, and outcomes was assessed through binary logistic regression and classification and regression tree (CART) analysis. Our findings revealed elevated levels of IL-6 in serum as well as increased expression of hepcidin (HAMP), transferrin (TF), and transferrin receptor-1 (TFR1) mRNA in JEV infection cases. Moreover, we found a genetic variation in TF (rs4481157) associated with clinical symptoms of meningoencephalitis. CART analysis indicates that individuals with the wild-type TF genotype are more susceptible to moderate JEV infection, while those with the homozygous type are in the high-risk group to develop a severe JEV condition. In summary, the study highlights that JEV infection induces alteration in both IL-6 levels and iron regulatory processes, which play pivotal roles in the development of JEV disease pathologies.","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":" ","pages":"596-602"},"PeriodicalIF":3.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71425509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulation of Viability, Proliferation, and Stemness by Rosmarinic Acid in Medulloblastoma Cells: Involvement of HDACs and EGFR. 迷迭香酸对髓母细胞瘤细胞活力、增殖和稳定性的调节：HDAC和EGFR的参与。

IF 3.5 4区医学

NeuroMolecular Medicine Pub Date : 2023-12-01 Epub Date: 2023-09-23 DOI: 10.1007/s12017-023-08758-x

Alice Laschuk Herlinger, Gustavo Lovatto Michaelsen, Marialva Sinigaglia, Lívia Fratini, Gabriela Nogueira Debom, Elizandra Braganhol, Caroline Brunetto de Farias, Algemir Lunardi Brunetto, André Tesainer Brunetto, Mariane da Cunha Jaeger, Rafael Roesler

{"title":"Modulation of Viability, Proliferation, and Stemness by Rosmarinic Acid in Medulloblastoma Cells: Involvement of HDACs and EGFR.","authors":"Alice Laschuk Herlinger, Gustavo Lovatto Michaelsen, Marialva Sinigaglia, Lívia Fratini, Gabriela Nogueira Debom, Elizandra Braganhol, Caroline Brunetto de Farias, Algemir Lunardi Brunetto, André Tesainer Brunetto, Mariane da Cunha Jaeger, Rafael Roesler","doi":"10.1007/s12017-023-08758-x","DOIUrl":"10.1007/s12017-023-08758-x","url":null,"abstract":"Medulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognoses. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients' quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC50 = 168 μM) and D283 (IC50 = 334 μM) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression of CDKN1A/p21, reduced expression of SOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB.","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":" ","pages":"573-585"},"PeriodicalIF":3.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41127157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting Pericytes for Functional Recovery in Ischemic Stroke. 以缺血性中风的周细胞为靶点促进功能恢复

IF 3.5 4区医学

NeuroMolecular Medicine Pub Date : 2023-12-01 Epub Date: 2023-05-11 DOI: 10.1007/s12017-023-08748-z

Shuqi Hu, Bingjie Yang, Song Shu, Xudong He, Hongfei Sang, Xuemei Fan, Hao Zhang

引用次数: 0

A Missense Variant in AIFM1 Caused Mitochondrial Dysfunction and Intolerance to Riboflavin Deficiency. AIFM1 的一个缺失变异导致线粒体功能障碍和核黄素缺乏不耐受。

IF 3.5 4区医学

NeuroMolecular Medicine Pub Date : 2023-12-01 Epub Date: 2023-08-21 DOI: 10.1007/s12017-023-08750-5

Ying Zhao, Yan Lin, Bin Wang, Fuchen Liu, Dandan Zhao, Wei Wang, Hong Ren, Jiayin Wang, Zhihong Xu, Chuanzhu Yan, Kunqian Ji

{"title":"A Missense Variant in AIFM1 Caused Mitochondrial Dysfunction and Intolerance to Riboflavin Deficiency.","authors":"Ying Zhao, Yan Lin, Bin Wang, Fuchen Liu, Dandan Zhao, Wei Wang, Hong Ren, Jiayin Wang, Zhihong Xu, Chuanzhu Yan, Kunqian Ji","doi":"10.1007/s12017-023-08750-5","DOIUrl":"10.1007/s12017-023-08750-5","url":null,"abstract":"AIFM1 is a mitochondrial flavoprotein involved in caspase-independent cell death and regulation of respiratory chain complex biogenesis. Mutations in the AIFM1 gene have been associated with multiple clinical phenotypes, but the effectiveness of riboflavin treatment remains controversial. Furthermore, few studies explored the reasons underlying this controversy. We reported a 7-year-old boy with ataxia, sensorimotor neuropathy and muscle weakness. Genetic and histopathological analyses were conducted, along with assessments of mitochondrial function and apoptosis level induced by staurosporine. Riboflavin deficiency and supplementation experiments were performed using fibroblasts. A missense c.1019T > C (p. Met340Thr) variant of AIFM1 was detected in the proband, which caused reduced expression of AIFM1 protein and mitochondrial dysfunction as evidenced by downregulation of mitochondrial complex subunits, respiratory deficiency and collapse of ΔΨm. The proportion of apoptotic cells in mutant fibroblasts was lower than controls after induction of apoptosis. Riboflavin deficiency resulted in decreased AIFM1 protein levels, while supplementation with high concentrations of riboflavin partially increased AIFM1 protein levels in variant fibroblasts. In addition, mitochondrial respiratory function of mutant fibroblasts was partly improved after riboflavin supplementation. Our study elucidated the pathogenicity of the AIFM1 c.1019T > C variant and revealed mutant fibroblasts was intolerant to riboflavin deficiency. Riboflavin supplementation is helpful in maintaining the level of AIFM1 protein and mitochondrial respiratory function. Early riboflavin treatment may serve as a valuable attempt for patients with AIFM1 variant.","PeriodicalId":19304,"journal":{"name":"NeuroMolecular Medicine","volume":" ","pages":"489-500"},"PeriodicalIF":3.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10407320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0