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tdp-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis

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Translational Neurodegeneration 2022年第1期11卷 46-69页

作者： Sarah Lépine Maria José Castellanos-Montiel Thomas Martin Durcan The Neuro’s Early Drug Discovery Unit(EDDU) Department of Neurology and NeurosurgeryMontreal Neurological Institute-HospitalMcGill University3801 University StreetMontrealQC H3A 2B4Canada Faculty of Medicine and Health Sciences McGill University3605 De La MontagneMontrealQC H3G 2M1Canada

Amyotrophic lateral sclerosis(ALS)is a disease characterized by upper and lower motor neuron(MN)loss with a signature feature of cytoplasmic aggregates containing tdp-43,which are detected in nearly all patients.Mutations in the gene that encodes tdp-43(TARBDP)are known to result in both familial and sporadic ALS.In ALS,disruption of neuro-muscular junctions(NMJs)constitutes a critical event in disease pathogenesis,leading to denervation atrophy,motor impairments and disability.Morphological defects and impaired synaptic transmission at NMJs have been reported in several tdp-43 animal models and in vitro,linking tdp-43 dysregulation to the loss of NMJ integrity in ALS.Through the lens of the dying-back and dying-forward hypotheses of ALS,this review discusses the roles of tdp-43 related to synaptic function,with a focus on the potential molecular mechanisms occurring within MNs,skeletal muscles and glial cells that may contribute to NMJ disruption in ALS.

关键词： Amyotrophic lateral sclerosis Denervation Neuromuscular junction tdp-43 Dying-back Dying-forward

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散发性包涵体肌炎1例

中国神经精神疾病杂志 2024年第2期50卷 114-118页

作者：林晓丹陈龙郑富泽郑颖曾明慧林锋林珉婷王柠王志强福建医科大学附属第一医院神经内科神经病学研究所福建省分子神经病学重点实验室福州350005 福建医科大学附属闽东医院神经内科福建医科大学附属第一医院滨海院区国家区域医疗中心神经内科

回顾性分析1例散发性包涵体肌炎(sporadic inclusion body myositis, sIBM)患者的临床表现、肌肉影像学、肌肉组织病理学与免疫病理学、超微结构及肌炎抗体谱等特点。患者,男,69岁,双下肢无力3年余,逐渐出现握力差、吞咽费力感;肌酸激... 详细信息

回顾性分析1例散发性包涵体肌炎(sporadic inclusion body myositis, sIBM)患者的临床表现、肌肉影像学、肌肉组织病理学与免疫病理学、超微结构及肌炎抗体谱等特点。患者,男,69岁,双下肢无力3年余,逐渐出现握力差、吞咽费力感;肌酸激酶轻度升高;EMG示肌源性损害;大腿肌肉MRI示双侧股外侧肌、股内侧肌及股中间肌脂肪浸润,股直肌、半膜肌及半腱肌相对保留;肌肉组化示中度炎症性肌病改变,伴镶边空泡及p62(Sequestosome-1)、tdp-43(TAR DNA binding protein-43)在胞内聚集;电镜下肌丝间可见中等量涡轮状髓样小体;肌炎抗体谱示cN1A(cytoplasmic 5'-nucleotidase 1A)抗体阳性。sIBM的起病年龄及肌群受累模式有其特殊性,但早期临床表现缺乏特异性,诊断困难,分子生物标记物有助于确诊及机制研究。

关键词：散发性包涵体肌炎病理学 p62 tdp-43 cN1A抗体

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Phosphorylated tdp-43 Staging of Primary Age-Related Tauopathy

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Neuroscience Bulletin 2019年第2期35卷 183-192页

作者： Xiaoling Zhang Bing Sun Xing Wang Hui Lu Fangjie Shao Annemieke J.M.Rozemuller Huazheng Liang Chong Liu Jiadong Chen Manli Huang Keqing Zhu China Brain Bank and Department of Neurology in Second Affiliated Hospital Key Laboratory of Medical Neurobiology of Zhejiang ProvinceDepartment of NeurobiologyZhejiang University School of Medicine Department of Pathology Zhejiang University School of Medicine Department of Pathology Amsterdam NeuroscienceVU University Medical Center Brain Structure and Function Group Neuroscience Research Australia Department of Psychiatry First Affiliated HospitalZhejiang University School of Medicine

Primary age-related tauopathy(PART) is characterized by tau neurofibrillary tangles(NFTs) in the absence of amyloid plaque pathology. In the present study,we analyzed the distribution patterns of phosphorylated43-kDa TAR DNA-binding protein(ptdp-43) in the brains of patients with PART. Immunohistochemistry and immunofluorescence double-labeling in multiple brain regions was performed on brain tissues from PART,Alzheimer's disease(AD), and aging control cases. We examined the regional distribution patterns of ptdp-43 intraneuronal inclusions in PART with Braak NFT stages[ 0 and B IV, and a Thal phase of 0(no beta-amyloid present). We found four stages which indicated potentially sequential dissemination of ptdp-43 in PART. Stage I was characterized by the presence of ptdp-43 lesions in the amygdala, stage II by such lesions in the hippocampus,stage III by spread of ptdp-43 to the neocortex, and stage IV by ptdp-43 lesions in the putamen, pallidum, and insular cortex. In general, the distribution pattern of ptdp-43 pathology in PART cases was similar to the early tdp-43 stages reported in AD, but tended to be more restricted to the limbic system. However, there were some differences in the distribution patterns of ptdp-43 between PART and AD, especially in the dentate gyrus of the hippocampus. Positive correlations were found in PART between the Braak NFT stage and the ptdp-43 stage and density.

关键词： tdp-43 Primary age-related tauopathy Alzheimer's disease Neurofibrillary tangle Hippocampus

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tdp-43 regulates cancer-associated microRNAs

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Protein & Cell 2018年第10期9卷 848-866页

作者： Xiaowei Chen Zhen Fan Warren McGee Mengmeng Chen Ruirui Kong Pushuai Wen Tengfei Xiao Xiaomin Chen Jianghong Liu Li Zhu Runsheng Chen Jane Y. Wu CAS Key Laboratory of RNA Biology Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China Research Network of Computational Biology RNCB Beijing 100101 China Core Facility for Protein Research institute of Biophysics Chinese Academy of Sciences Beijing 100101 China State Key Laboratory of Brain and Cognitive Science Institute of Biophysics Chinese Academy of Sciences Beijing 100101China Department of Neurology Center for Genetic Medicine Lurie Cancer Center Northwestern University Feinberg School ofMedicine Chicago IL 60611 USA Guangdong Geneway Decoding Bio-Tech Co. Ltd Foshan 528316 China

regulation of miRNA genes contributes to pathogenesis of a wide range of human diseases, including cancer. The TAR DNA binding protein 43 （tdp- 43）, a RNAJDNA binding protein associated with neu- rodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs regulated by tdp- 43 using RNA-Seq coupled with an siRNA-mediated knockdown approach. tdp-43 knockdown affected the expression of a number of miRNAs. In addition, tdp-43 down-regulation led to alterations in the patterns of dif- ferent isoforms of miRNAs （isomiRs） and miRNA arm selection, suggesting a previously unknown role of tdp- 43 in miRNA processing. A number of tdp-43 associ- ated miRNAs, and their candidate target genes, are associated with human cancers. Our data reveal highly complex roles of tdp-43 in regulating different miRNAs and their target genes. Our results suggest that tdp-43 may promote migration of lung cancer cells by regulat- ing miR-423-3p. In contrast, tdp-43 increases miR-500a- 3p expression and binds to the mature miR-500a-3p sequence. Reduced expression of miR-500a-3p is associated with poor survival of lung cancer patients,suggesting that tdp-43 may have a suppressive role in cancer by regulating miR-500a-3p. Cancer-associated genes LIF and PAPPA are possible targets of miR-500a- 3p. Our work suggests that tdp-43-regulated miRNAs may play multifaceted roles in the pathogenesis of cancer.

关键词： tdp-43 miRNA cancer migration prognosis

Maintaining the balance of tdp-43,mitochondria,and autophagy:a promising therapeutic strategy for neurodegenerative diseases

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Translational Neurodegeneration 2020年第4期9卷 509-524页

作者： Chunhui Huang Sen Yan Zaijun Zhang Institute of New Drug Research Guangdong Province Key Laboratory of PharmacodynamicConstituents of Traditional Chinese Medicine and New Drug ResearchCollege of PharmacyJinan UniversityGuangzhou 510632China Ministry of Education CNS Regeneration Collaborative Joint Laboratory Guangdong-Hongkong-Macao Institute of CNS RegenerationJinan UniversityGuangzhou 510632China

Mitochondria are the energy center of cell operations and are involved in physiological functions and maintenance of metabolic balance and homeostasis in the body.Alterations of mitochondrial function are associated with a variety of degenerative and acute diseases.As mitochondria age in cells,they gradually become inefficient and potentially toxic Acute injury can trigger the permeability of mitochondrial membranes,which can lead to apoptosis or necrosis.Transactive response DNA-binding protein 43 kDa(tdp-43)is a protein widely present in cells.It can bind to RNA,regulate a variety of RNA processes,and play a role in the formation of multi-protein/RNA complexes.Thus,the normal physiological functions of tdp-43 are particularly important for cell survival.Normal tdp-43 is located in various subcellular structures including mitochondria,mitochondrial-associated membrane,RNA particles and stress granules to regulate the endoplasmic reticulum-mitochondrial binding,mitochondrial protein translation,and mRNA transport and translation.Importantly,tdp-43 is associated with a variety of neurodegenerative diseases,including amyotrophic lateral sclerosis,frontotemporal dementia and Alzheimer's disease,which are characterized by abnormal phosphorylation,ubiquitination,lysis or nuclear depletion of tdp-43 in neurons and glial cells.Although the pathogenesis of tdp-43 proteinopathy remains unknown,the presence of pathological tdp-43 inside or outside of mitochondria and the functional involvement of tdp-43 in the regulation of mitochondrial morphology,transport,and function suggest that mitochondria are associated with tdp-43-related diseases.Autophagy is a basic physiological process that maintains the homeostasis of cells,including targeted clearance of abnormally aggregated proteins and damaged organelles in the cytoplasm;therefore,it is considered protective against neurodegenerative diseases.However,the combination of abnormal tdp-43 aggregation,mitochondrial dysfunction,and insufficient autophagy can lead to a variety o

关键词： tdp-43 Mitochondria Autophagy/mitophagy Neurodegeneration

tdp-43异常聚集介导的线粒体损伤在CCl4诱导的肝纤维化中的作用及其机制研究

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TDP-43异常聚集介导的线粒体损伤在CCl4诱导的肝纤维化中的作用及...

作者：雍慧山东大学

学位级别：硕士

研究目的肝纤维化是慢性肝病发展过程中肝脏细胞反复破坏后再生,细胞外基质在肝脏中弥漫性沉积的病理生理过程。肝脏作为富含线粒体的器官之一,健康的线粒体网络对维持肝脏正常功能至关重要。病理因素引起的线粒体损伤可导致mtDNA外泄,... 详细信息

研究目的肝纤维化是慢性肝病发展过程中肝脏细胞反复破坏后再生,细胞外基质在肝脏中弥漫性沉积的病理生理过程。肝脏作为富含线粒体的器官之一,健康的线粒体网络对维持肝脏正常功能至关重要。病理因素引起的线粒体损伤可导致mtDNA外泄,通过cGAS-STING途径触发炎症反应,促进肝纤维化的进展。最近研究表明,线粒体上tdp-43的异常蓄积会干扰神经细胞线粒体的正常功能,诱导神经炎症反应,参与神经退行性疾病的发生。然而,目前国内外尚未见tdp-43聚集诱导线粒体损伤参与肝纤维化进程的报道。因此,在本研究中,我们利用CCl4染毒建立肝纤维化小鼠模型,检测肝脏组织的线粒体形态与功能变化、tdp-43的表达和分布、炎症反应以及cGAS-STING通路的激活情况。在此基础上,利用雷帕霉素(Rapamycin,RAPA)建立自噬干预模型,观测药物干预对CCl4诱导的肝纤维化和线粒体损伤的影响,以此探究tdp-43异常蓄积造成的线粒体损伤在肝纤维化中的作用及其可能机制,以期为肝纤维化提供新的治疗靶点。研究方法本研究选用雄性C57BL/6小鼠,慢性染毒CC14建立小鼠肝纤维化模型和RAPA干预模型,探索tdp-43异常蓄积介导的线粒体损伤在肝纤维化中的作用及其分子机制。利用全自动生化仪测定血清中ALT、AST水平;采用H&E染色、天狼星红染色以及Masson染色检测肝纤维化病理改变;利用透射电镜观测线粒体超微结构的损伤;采用Western Blot和免疫荧光染色技术检测纤维化标志蛋白、炎症相关蛋白、cGAS-STING信号通路关键分子的表达以及tdp-43在胞质和线粒体的表达和定位情况;采用RT-PCR技术测定胞质mtDNA含量。研究结果(1)慢性CCl4暴露诱导小鼠肝脏组织α-SMA、Col-Ⅰ和TGF-β1蛋白表达水平显著升高。透射电镜观察发现线粒体形态异常,Western Blot检测显示PINK1、Parkin水平升高,同时RT-PCR发现胞质中mtDNA含量升高。(2)CC14暴露诱导肝脏炎性信号通路的激活。肝脏中NLRP3、caspase1和IL-1β表达水平显著升高,同时cGAS-STING信号通路关键分子cGAS、STING、IRF3表达水平以及下游NF-κB核转位明显增加。(3)CC14暴露诱导肝纤维化过程中肝细胞tdp-43表达升高,且与线粒体共定位显著增加,提示tdp-43在线粒体蓄积。(4)RAPA处理可有效促进肝纤维化的消退,缓解线粒体损伤。(5)RAPA可有效促进CCl4诱导的线粒体中异常蓄积的tdp-43的清除。同时RAPA能抑制NLRP3炎性小体和cGAS-STING信号通路关键分子的表达。研究结论(1)CC14染毒引起tdp-43在肝细胞线粒体蓄积,诱导线粒体损伤。(2)线粒体损伤可激活NLRP3炎性小体,同时线粒体损伤释放的mtDNA可激活cGAS-STING信号通路,共同诱发炎症反应,促进肝纤维化形成。(3)RAPA干预可通过激活线粒体自噬清除受损线粒体及异常蓄积的tdp-43,从而缓解炎症反应,促进肝纤维化消退。

关键词：肝纤维化线粒体自噬 cGAS-STING信号通路炎症反应 tdp-43

tdp43/HDAC6/Prdx1通路通过调节炎症和氧化应激参与OSA的认知损害

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TDP43/HDAC6/Prdx1通路通过调节炎症和氧化应激参与OSA的认知损害

作者：欧彦汝中南大学

学位级别：硕士

第一部分tdp43/HDAC6/Prdx1通路与OSA患者认知功能损害相关目的:既往研究发现神经炎症和氧化应激参与阻塞性睡眠呼吸暂停(obstructive sleep apnea,OSA)患者认知功能障碍的发病过程。然而,其潜在的调控机制尚不明确。本研究旨在评估OSA... 详细信息

第一部分tdp43/HDAC6/Prdx1通路与OSA患者认知功能损害相关目的:既往研究发现神经炎症和氧化应激参与阻塞性睡眠呼吸暂停(obstructive sleep apnea,OSA)患者认知功能障碍的发病过程。然而,其潜在的调控机制尚不明确。本研究旨在评估OSA患者和健康参与者认知功能的差异;检测OSA患者及健康参与者外周血单个核细胞(peripheral blood mononuclear cell,PBMC)中反式激活调节DNA结合蛋白43(TAR DNA-binding protein 43,tdp-43)、组蛋白去乙酰酶6(Histone deacetylase 6,HDAC6)和过氧化氧还蛋白(peroxiredoxin,Prdx1)的表达情况,并分析其与睡眠呼吸参数及认知功能的相关性。方法:所有受试者接受多导睡眠监测以诊断OSA,采用蒙特利尔认知量表(montreal cognitive assessment,Mo CA)和简易精神状态检查量表(mini-mental state examination,MMSE)评估认知功能。重度OSA患者接受持续气道正压通气(continuous positive airway pressure,CPAP)治疗并定期随访,记录患者治疗的依从性。经过12周的CPAP治疗后,要求患者回到医院,再次评估病情和认知功能。采集受试者治疗前后的外周血以分离单个核细胞,通过western blot检测相关目的蛋白的表达改变。结果:根据呼吸暂停低通气指数(apnea-hypopnea index,AHI)结果将受试者分为3组:健康对照组(n=20)、轻-中度OSA组(n=20)和重度OSA组(n=20)。OSA患者的Mo CA评分和MMSE评分均低于健康对照组,与AHI、氧减饱和指数(oxygen desaturation index,ODI)、艾普沃斯嗜睡量表(Epworth Sleepiness Scale,ESS)呈负相关,且MMSE评分与LSa O呈正相关。OSA患者PBMC中tdp-43、HDAC6蛋白表达升高,而Prdx1表达下调。并且tdp-43和HDAC6的表达与AHI和ODI呈正相关,其中HDAC6的表达与MSa O呈负相关;Prdx1的表达与AHI和ODI呈负相关,而与LSa O、MSa O呈正相关。CPAP治疗12周后,重度OSA患者的认知功能显著改善,tdp-43、HDAC6及Prdx1蛋白的表达部分逆转。同时,OSA患者中tdp-43、HDAC6蛋白表达与Mo CA和MMSE评分呈负相关,而Prdx1蛋白表达与Mo CA和MMSE评分呈正相关。结论:OSA患者PBMC中tdp-43、HDAC6和Prdx1蛋白表达改变与疾病严重程度以及认知功能密切相关。第二部分tdp-43/HDAC6/Prdx1通路调节小胶质细胞炎症和氧化应激目的:在细胞水平探究tdp-43/HDAC6/Prdx1通路是否参与调控神经炎症和氧化应激。方法:体外培养人小胶质细胞克隆3细胞(human microglial clone3 cell,HMC3),采用不同浓度的脂多糖(lipopolysaccharide,LPS)干预24小时以模拟神经炎症反应。使用过表达质粒上调tdp-43的表达,使用HDAC6抑制剂Tubacin抑制HDAC6的表达,使用si RNA干扰tdp43和Prdx1的表达。采用western blot检测tdp43、HDAC6、Prdx1蛋白表达;采用ELISA试剂盒检测细胞培养上清液中白介素(interleukin,IL)-6、IL-8的表达以评估炎症水平;同时检测上清液中超氧化物歧化酶(superoxide dismutase,SOD)、过氧化氢酶(catalase,CAT)及丙二醛(malondialdehyde,MDA)以评估氧化应激水平。结果:(1)LPS处理HMC3细胞后,细胞培养上清液中炎症因子IL-6、IL-8增加,脂质过氧化物MDA增加,而抗氧化酶SOD和CAT减少,且具有剂量依赖性递增/递减的特性。(2)LPS处理HMC3细胞后,tdp-43和HDAC6蛋白表达增加,而Prdx1蛋白表达下降,呈剂量依赖性。(3)使用si-tdp-43干扰tdp-43的表达,并给予LPS干预,结果显示抑制tdp-43逆转了LPS诱导的HDAC6表达升高,同时减轻了炎症和氧化应激的水平。(4)使用Tubacin抑制HDAC6的表达,并给予LPS干预,结果显示Tubacin显著抑制LPS诱导的HDAC6表达升高,同时上调Prdx1的表达水平,并且减轻炎症和氧化应激反应;而转染si RNA干扰Prdx1的表达后Prdx1的表达水平较前明显下降,而炎症和氧化应激水平较前明显升高,提示HDAC6可通过抑制Prdx1促进炎症和氧化应激。(5)使用质粒过表达tdp-43,结果显

关键词：阻塞性睡眠呼吸暂停炎症氧化应激认知 tdp-43 HDAC6 Prdx1

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tdp-43在缺血性脑卒中的作用

中国组织化学与细胞化学杂志 2023年第4期32卷 418-423,441页

作者：李钇朋闫文静章帆舒渝茜何治三峡大学国家中医药管理局中药药理科研三级实验室宜昌443002 三峡大学健康医学院宜昌443002

tdp-43(Transactive response DNA binding protein 43, tdp-43)最初被认为是神经退行性疾病的病理学标记蛋白,研究发现其参与脑缺血损伤的发生发展。在现有研究的基础上,简要介绍tdp-43的结构与功能以及tdp-43在脑缺血后的表达变化及... 详细信息

tdp-43(Transactive response DNA binding protein 43, tdp-43)最初被认为是神经退行性疾病的病理学标记蛋白,研究发现其参与脑缺血损伤的发生发展。在现有研究的基础上,简要介绍tdp-43的结构与功能以及tdp-43在脑缺血后的表达变化及其在脑缺血后调节炎症反应、线粒体功能障碍、自噬等方面的作用。

关键词： tdp-43 脑缺血缺血性脑卒中脑卒中

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tdp-43通过调控脂代谢基因ABHD2促进肝癌发生与发展分子机制研究

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TDP-43通过调控脂代谢基因ABHD2促进肝癌发生与发展分子机制研究

作者：王相允新乡医学院

学位级别：硕士

背景肝细胞癌（以下简称肝癌）是全球癌症相关死亡的第三大原因。tdp-43作为RNA/DNA结合蛋白,在癌症进展中至关重要。然而,其在肝癌中的作用及相关机制尚未完全阐明。前期研究发现脂代谢调控子ABHD2的m RNA序列中可能存在tdp-43蛋白的... 详细信息

背景肝细胞癌（以下简称肝癌）是全球癌症相关死亡的第三大原因。tdp-43作为RNA/DNA结合蛋白,在癌症进展中至关重要。然而,其在肝癌中的作用及相关机制尚未完全阐明。前期研究发现脂代谢调控子ABHD2的m RNA序列中可能存在tdp-43蛋白的结合位点。而tdp-43与ABHD2在肝癌中的关系迄今未有报道。目的本研究旨在探究tdp-43在肝癌发生发展过程中发挥的重要作用,并进一步阐明tdp-43通过调控脂代谢相关基因ABHD2促进肝癌恶性进展的分子机制,从而为肝癌的靶向治疗提供崭新思路。方法（1）细胞转染si RNA或过表达质粒,集落形成实验检测tdp-43对肝癌细胞增殖的影响;流式细胞术、WB、q PCR检测tdp-43对凋亡能力的影响。（2）裸鼠原位肝癌模型验证tdp-43对肝癌增殖和凋亡能力的影响。（3）生物数据库分析tdp-43与临床肝癌预后的关系。（4）RNA-seq分析敲低tdp-43后的表达差异基因及相关通路,结合q PCR筛选tdp-43下游靶基因。（5）q PCR、WB检测tdp-43对ABHD2表达水平的影响;IHC评估tdp-43与ABHD2的相关性。（6）RIP验证tdp-43与ABHD2 m RNA是否存在相互作用。敲低tdp-43后,用放线菌素D处理细胞,检测ABHD2 m RNA水平的变化。（7）双荧光素酶报告基因系统检测tdp-43对ABHD2 m RNA 3’UTR报告基因载体的荧光素酶活性的影响;结合ABHD2的m RNA序列分析tdp-43的结合位点。分别删除两个潜在结合位点后,再次检测荧光活性。（8）试剂盒检测ABHD2对肝癌细胞脂代谢及活性氧含量的影响。CCK8、克隆形成、流式细胞术、WB检测ABHD2对肝癌细胞增殖、凋亡能力的影响。（9）在肝癌细胞中敲低tdp-43后过表达ABHD2检测肝癌细胞的增殖、凋亡能力及脂代谢和活性氧水平的变化。（10）裸鼠原位肝癌模型检测过表达ABHD2能否逆转tdp-43缺失引起的增殖抑制和凋亡促进。结果（1）敲低tdp-43后,肝癌细胞的增殖能力减弱,凋亡水平增加。过表达tdp-43癌细胞增殖能力增强,凋亡水平下降。（2）体内实验证明敲低tdp-43抑制小鼠肿瘤生长,促进肿瘤凋亡。（3）GEO数据库提示tdp-43在肝癌中高表达;GEPIA和Kaplan-Meier Plotter生物数据库显示tdp-43的表达水平与肝癌患者的总生存率（P=0.00059）及无复发生存率（P=0.022）呈负相关。（4）RNA-seq显示tdp-43与脂代谢通路相关,敲低tdp-43后ABHD2显著下调。q PCR初步确定ABHD2为tdp-43的下游靶基因。（5）敲低tdp-43后,ABHD2的m RNA和蛋白表达水平均下调,过表达tdp-43后,ABHD2的m RNA和蛋白表达水平均增加。tdp-43与ABHD2在小鼠肿瘤组织及临床肝癌组织芯片中的表达存在很高相关性。（6）tdp-43与ABHD2 m RNA存在相互作用。敲低tdp-43,ABHD2 m RNA的稳定性下降。（7）敲低tdp-43,ABHD2 3’UTR报告基因载体的荧光素酶活性减少;过表达tdp-43,活性增加。但敲低或过表达tdp-43均不能改变删除位点1后的ABHD2 3’UTR报告基因载体的荧光素酶活性。（8）敲低ABHD2,肝癌细胞内FFA含量减少,ROS水平下降,细胞增殖能力减弱,凋亡水平增加。（9）敲低tdp-43后,肝癌细胞的FFA含量,ROS水平和增殖能力减弱,凋亡能力增加,而过表达ABHD2后,上述趋势被逆转。（10）过表达ABHD2可以改善tdp-43缺失对肝癌细胞增殖的抑制和凋亡的促进,并有效缓解裸鼠肿瘤组织内FFA的下调。结论tdp-43通过与下游靶基因ABHD2 m RNA 3’UTR区的位点1结合,增强m RNA的稳定性,促进ABHD2的表达。在肝癌中,tdp-43通过ABHD2影响脂代谢,进而促进肝癌细胞增殖,抑制肝癌细胞凋亡,最终影响肝癌的发生发展。

关键词： tdp-43 ABHD2 凋亡脂代谢肝癌