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PINK1 mediates neuronal survival in monkey

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Protein & Cell 2022年第1期13卷 4-5页

作者： Zhiyu Sun Jiangyu Ye Junying Yuan Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 201210China

Parkinson's disease(PD)is one of the most common neu-rodegenerative diseases with progressive motor dysfunction and pathologically characterized by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain and the development of neuronal Lewy bodies.Autosomal recessive mutations in the gene PINK1 leads to inherited idiopathic PD.PINK1 is known to regulate PARKIN translocation upon mitochondrial damage which drives their removal via selective autophagy,a process known as mito-phagy(Pickrell and Youle 2015;Cummins and Gotz 2018).While mitochondrial defects had been noted in postmortem studies of patient brain samples with PD,there is a continuing debate as how mutations in PINK1 may lead to selective neuronal death in the substantia nigra.

关键词： PINK1 PARK degeneration

基于PINK1-Parkin介导的线粒体自噬研究当归芍药散对AD大鼠的影响

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中国中药杂志 2023年第2期48卷 534-541页

作者：杨苗于文静贺春香金怡杰李泽李平邓思思易亚乔成绍武宋祯彦湖南中医药大学中西医结合心脑疾病防治湖南省重点实验室湖南长沙410208

基于PINK1-Parkin信号通路,探讨当归芍药散对链脲佐菌素(streptozocin,STZ)诱导的阿尔茨海默病(Alzheimer′s disease,AD)大鼠模型线粒体自噬影响的作用机制。通过双侧侧脑室注射STZ构建AD大鼠模型,实验分为正常组、模型组、当归芍药散... 详细信息

基于PINK1-Parkin信号通路,探讨当归芍药散对链脲佐菌素(streptozocin,STZ)诱导的阿尔茨海默病(Alzheimer′s disease,AD)大鼠模型线粒体自噬影响的作用机制。通过双侧侧脑室注射STZ构建AD大鼠模型,实验分为正常组、模型组、当归芍药散低剂量组(12 g·kg^(-1)·d^(-1))、当归芍药散中剂量组(24 g·kg^(-1)·d^(-1))、当归芍药散高剂量组(36 g·kg^(-1)·d^(-1))。Morris水迷宫实验检测大鼠学习记忆功能,透射电镜和免疫荧光共定位检测线粒体自噬情况,免疫印迹法(Western blot)检测PTEN诱导的激酶1(PTEN induced putative kinase 1,PINK1)、Parkin、LC3BⅠ/LC3BⅡ、p62蛋白的表达。与正常组比较,模型组大鼠学习记忆功能显著降低(P1),PINK1、Parkin表达降低(P1);与模型组比较,当归芍药散中、高剂量组能显著改善AD大鼠的学习记忆功能,主要表现为逃避潜伏期缩短、目标象限停留时间延长、穿过平台的次数增加(P1);线粒体自噬显著增多(PPINK1、Parkin表达显著升高,而LC3BⅠ/LC3BⅡ、p62的表达显著降低(P1)。结果表明,当归芍药散可能通过促进PINK1-Parkin介导的线粒体自噬将受损的线粒体清除,改善线粒体功能,从而发挥神经保护作用。

关键词：线粒体自噬当归芍药散阿尔茨海默病 PINK1 Parkin

人参皂苷Rg_(1)通过激活PINK1/parkin增强线粒体自噬保护Aβ损伤的PC12细胞

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中国中药杂志 2022年第2期47卷 484-491页

作者：李和梅蒋怡萱黄盼玲李泊村潘子瑜李宇清夏星广西中医药大学药学院广西南宁530200 广西中医药大学公共卫生与管理学院广西南宁530200 广西中医药大学广西高校中药药理重点实验室广西南宁530200

阿尔茨海默病(Alzheimer′s disease,AD)患者脑中的β-淀粉样蛋白(amyloidβ-protein,Aβ)沉积是造成神经元线粒体损伤的直接原因。线粒体自噬是清除受损线粒体,保护神经细胞的重要方式。人参皂苷Rg_(1)具有神经保护作用,在防治AD方面... 详细信息

阿尔茨海默病(Alzheimer′s disease,AD)患者脑中的β-淀粉样蛋白(amyloidβ-protein,Aβ)沉积是造成神经元线粒体损伤的直接原因。线粒体自噬是清除受损线粒体,保护神经细胞的重要方式。人参皂苷Rg_(1)具有神经保护作用,在防治AD方面有广阔的应用前景,但人参皂苷Rg_(1)减轻Aβ造成神经损伤的机制尚未阐明。为探讨人参皂苷Rg_(1)通过影响自噬保护神经细胞的作用机制,该文利用Aβ_(25-35)诱导PC12细胞损伤模型,观察了人参皂苷Rg_(1)的保护作用及对细胞自噬的影响,运用自噬诱导剂雷帕霉素和自噬抑制剂氯喹验证Rg_(1)的神经保护作用与自噬的相关性。发现人参皂苷Rg_(1)能够增强Aβ损伤PC12细胞的活力,并提高线粒体膜电位,减轻Aβ引起的线粒体损伤,这种保护效果能被自噬抑制剂氯喹阻断;人参皂苷Rg_(1)还能增加LC3Ⅱ/Ⅰ蛋白比例并促进p62蛋白消耗,同时增加PINK1及parkin蛋白,减少线粒体自噬接头蛋白OPTN的数量,表现出增强PC12细胞的自噬水平的作用。在运用PINK1 shRNA减低线粒体自噬调控位点PINK1的表达后,人参皂苷Rg_(1)不能再增加PINK1及其下游parkin的表达,并且不能显著影响线粒体自噬接头蛋白NDP52的数量,但其增强自噬的作用没有受到明显影响,仍能够显著增加LC3Ⅱ/Ⅰ比例,并且促进OPTN的消耗。该文研究表明人参皂苷Rg_(1)能促进Aβ损伤的PC12细胞的自噬水平,此外还可能通过促进PINK1介导的线粒体自噬,减轻线粒体受到的损伤,这可能是其改善Aβ造成的细胞损伤的作用机制之一。

关键词：人参皂苷Rg_(1) Aβ淀粉样蛋白线粒体自噬 PINK1

PINK1/Parkin信号通过激活海马线粒体自噬介导脓毒症相关性脑病认知功能障碍

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中华危重病急救医学 2023年第4期35卷 381-386页

作者：冯悦戴宇麒郭姚邑姜帆廖洪森李浩甲鲍红光斯妍娜南京医科大学附属南京医院(南京市第一医院)麻醉科江苏南京210000

目的探讨磷酸酶及张力蛋白同源基因(PTEN)诱导激酶1(PINK1)/自噬相关蛋白Parkin通路对脓毒症相关性脑病(SAE)小鼠海马线粒体自噬和认知功能障碍的影响与可能机制。方法将80只雄性C57BL/6J小鼠按随机数字表法分为假手术(Sham)组、盲肠结... 详细信息

目的探讨磷酸酶及张力蛋白同源基因(PTEN)诱导激酶1(PINK1)/自噬相关蛋白Parkin通路对脓毒症相关性脑病(SAE)小鼠海马线粒体自噬和认知功能障碍的影响与可能机制。方法将80只雄性C57BL/6J小鼠按随机数字表法分为假手术(Sham)组、盲肠结扎穿孔术(CLP)组、转染PINK1质粒预处理组(p-PINK1+Sham组、p-PINK1+CLP组)和转染空载质粒对照组(p-vector+CLP组),每组16只。CLP各组小鼠行CLP制备SAE模型;Sham各组开腹后仅分离盲肠末端。p-PINK1预处理组分别于Sham或CLP术前24 h经侧脑室转染PINK1质粒;p-vector+CLP组转染空载质粒。各组小鼠均于术后7 d进行Morris水迷宫实验。取海马组织,苏木素-伊红(HE)染色后,光镜下观察病理学改变;醋酸铀-枸橼酸铅双染后,透射电镜下观察线粒体自噬情况;采用蛋白质免疫印迹试验(Western blotting)检测PINK1、Parkin、自噬相关蛋白Beclin1、白细胞介素(IL-6、IL-1β)和微管相关蛋白1轻链3(LC3)的表达。结果与Sham组比较,CLP组小鼠Morris水迷宫实验1~4 d逃避潜伏期明显延长,靶象限停留时间明显缩短,穿越平台次数明显减少;光镜下可见小鼠海马组织结构破坏,神经元细胞排列紊乱、细胞核固缩;透射电镜下可见肿胀变圆的线粒体及被双层膜或多层膜结构包裹的线粒体结构;且CLP组海马组织PINK1、Parkin、Beclin1、LC3Ⅱ/LC3Ⅰ比值、IL-6和IL-1β蛋白表达均明显上调。说明CLP诱导的脓毒症可激活炎症反应,引起PINK1/Parkin介导的线粒体自噬。与CLP组比较,p-PINK1+CLP组小鼠Morris水迷宫实验1~4 d逃避潜伏期明显缩短,靶象限停留时间明显延长,穿越平台次数明显增加;光镜下可见小鼠海马组织结构破坏程度明显减轻,少量细胞核固缩,未出现明显细胞水肿、变性和坏死;透射电镜下可见线粒体轻度肿胀和空泡样变性,被自噬体包裹的线粒体数量增加;且p-PINK1+CLP组海马组织PINK1、Parkin、Beclin1表达和LC3Ⅱ/LC3Ⅰ比值明显升高〔PINK1蛋白(PINK1/β-actin):1.95±0.17比1.74±0.15,Parkin蛋白(Parkin/β-actin):2.06±0.11比1.78±0.12,Beclin1蛋白(Beclin1/β-actin):2.11±0.12比1.67±0.10,LC3Ⅱ/LC3Ⅰ比值:3.63±0.12比2.27±0.10,均P1β释放明显减少〔IL-6蛋白(IL-6/β-actin):1.69±0.09比2.00±0.11,IL-1β蛋白(IL-1β/β-actin):1.11±0.12比1.65±0.12,均PPINK1蛋白可进一步激活线粒体自噬,减轻脓毒症引起的炎症反应。Sham组与p-PINK1+Sham组、CLP组与p-vector+CLP组上述病理学改变及相关指标差异均无统计学意义。结论PINK1高表达可通过上调Parkin进一步激活CLP引起的线粒体自噬,从而抑制炎症反应,减轻SAE小鼠认知功能损伤。

关键词：脓毒症相关性脑病炎症反应线粒体自噬 PINK1 Parkin

Co-editing PINK1 and DJ-1 Genes Via Adeno-Associated Virus-Delivered CRISPR/Cas9 System in Adult Monkey Brain Elicits Classical Parkinsonian Phenotype

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Neuroscience Bulletin 2021年第9期37卷 1271-1288页

作者： Hao Li Shihao Wu Xia Ma Xiao Li Tianlin Cheng Zhifang Chen Jing Wu Longbao Lv Ling Li Liqi Xu Wenchao Wang Yingzhou Hu Haisong Jiang Yong Yin Zilong Qiu Xintian Hu Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province Kunming Institute of ZoologyChinese Academy of Sciences650223 KunmingChina Institute of Neuroscience CAS Key Laboratory of Primate NeurobiologyState Key Laboratory of NeuroscienceChinese Academy of SciencesShanghai 200031China Institutes of Physical Science and Information Technology Anhui UniversityHefei 230601China Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 200031China National Resource Center for Non-human Primates Kunming Primate Research Centerand National Research Facility for Phenotypic and Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyChinese Academy of Sciences650107 KunmingChina Diagnostic Radiology Department 920 Hospital of the Joint Logistics Support Force of the PLAKunming 650032China Ultrasound diagnosis Department 920 Hospital of the Joint Logistics Support Force of the PLAKunming 650032China Sichuan Provincial People’s Hospital University of Electronic Science and Technology of ChinaChengdu 610072China Department of Rehabilitation Medicine The Second People’s Hospital of Yunnan ProvinceKunming 650021China National Clinical Research Center for Aging and Medicine Huashan HospitalFudan UniversityShanghai 200433China

Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras(SNs)of two monkey groups:an old group and a middle-aged group.After the operation,the old group exhibited all the classic PD symptoms,including bradykinesia,tremor,and postural instability,accompanied by key pathological hallmarks of PD,such as severe nigral dopaminergic neuron loss(>64%)and evidentα-synuclein pathology in the gene-edited SN.In contrast,the phenotype of their middle-aged counterparts,which also showed clear PD symptoms and pathological hallmarks,were less severe.In addition to the higher final total PD scores and more severe pathological changes,the old group were also more susceptible to gene editing by showing a faster process of PD progression.These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys.Taken together,this system can effectively develop a large number of genetically-edited PD monkeys in a short time(6–10 months),and thus provides a practical transgenic monkey model for future PD studies.

关键词： Parkinson’s disease Monkey Adeno-associated virus-delivered CRISPR/Cas9 PINK1 DJ-1 Parkinsonian phenotype

Deciphering the dual role and prognostic potential of PINK1 across cancer types

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Neural Regeneration Research 2021年第4期16卷 659-665页

作者： Katherine Dai Daniel P.Radin Donna Leonardi Department of Molecular Cellularand Developmental BiologyYale UniversityNew HavenCTUSA Department of Pharmacology Stony Brook University School of MedicineStony BrookNYUSA Bergen County Academies HackensackNJUSA

Metabolic rewiring and deregulation of the cell cycle are hallmarks shared by many cancers.Concerted mutations in key tumor suppressor genes,such as PTEN,and oncogenes predispose cancer cells for marked utilization of resources to fuel accelerated cell proliferation and chemotherapeutic resistance.Mounting research has demonstrated that PTEN-induced putative kinase 1(PINK1)acts as a pivotal regulator of mitochondrial homeostasis in several cancer types,a function that also extends to the regulation of tumor cell proliferative capacity.In addition,involvement of PINK1 in modulating inflammatory responses has been highlighted by recent studies,further expounding PINK1’s multifunctional nature.This review discusses the oncogenic roles of PINK1 in multiple tumor cell types,with an emphasis on maintenance of mitochondrial homeostasis,while also evaluating literature suggesting a dual oncolytic mechanism based on PINK1’s modulation of the Warburg effect.From a clinical standpoint,its expression may also dictate the response to genotoxic stressors commonly used to treat multiple malignancies.By detailing the evidence suggesting that PINK1 possesses distinct prognostic value in the clinical setting and reviewing the duality of PINK1 function in a context-dependent manner,we present avenues for future studies of this dynamic protein.

关键词： apoptosis cancer cell cycle inflammation metabolic stress mitochondral quality control mitophagy PINK1 tumor Warburg effect

PINK1 gene mutation by pair truncated sgRNA/Cas9-D10A in cynomolgus monkeys

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Zoological Research 2021年第4期42卷 469-477页

作者： Zhen-Zhen Chen Jian-Ying Wang Yu Kang Qiao-Yan Yang Xue-Ying Gu Da-Long Zhi Li Yan Cheng-Zu Long Bin Shen Yu-Yu Niu Faculty of Life Science and Technology Kunming University of Science and TechnologyKunmingYunnan 650500China State Key Laboratory of Primate Biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnan 650500China State Key Laboratory of Reproductive Medicine Department of Prenatal DiagnosisWomen’s Hospital of Nanjing Medical UniversityNanjing Maternity and Child Health HospitalNanjing Medical UniversityNanjingJiangsu 211166China Leon H Charney Division of Cardiology New York University School of MedicineNew YorkNY 10016USA Department of Dermatology Xijing HospitalFourth Military Medicine UniversityXi’anShaanxi 710032China

Mutations of PTEN-induced kinase I(PINK1)cause early-onset Parkinson’s disease(PD)with selective neurodegeneration in humans.However,current PINK1 knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients.This suggests that generating PINK1 disease models in non-human primates(NHPs)that are close to humans is essential to investigate the unique function of PINK1 in primate brains.Paired single guide RNA(sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9,both of which can reduce off-target effects without compromising on-target editing,are two optimized strategies in the CRISPR/Cas9 system for establishing disease animal models.Here,we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to target the PINK1 gene.We achieved precise and efficient gene editing of the target site in three newborn cynomolgus monkeys.The frame shift mutations of PINK1 in mutant fibroblasts led to a reduction in mRNA.However,western blotting and immunofluorescence staining confirmed the PINK1 protein levels were comparable to that in wild-type fibroblasts.We further reprogramed mutant fibroblasts into induced pluripotent stem cells(iPSCs),which showed similar ability to differentiate into dopamine(DA)neurons.Taken together,our results showed that co-injection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enabled the generation of human disease models in NHPs and target editing by pair truncated sgRNA/Cas9-D10A in PINK1 gene exon 2 did not impact protein expression.

关键词： Cas9-D10A Cynomolgus PINK1

Parkinson’s disease-associated VPS35 mutant reduces mitochondrial membrane potential and impairs PINK1/Parkinmediated mitophagy

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Translational Neurodegeneration 2021年第2期10卷 240-256页

作者： Kai Yu Ma Michiel R.Fokkens Fulvio Reggiori Muriel Mari Dineke S.Verbeek Department of Genetics University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands Department of Biomedical Sciences of Cells and Systems University of GroningenUniversity Medical Center GroningenGroningenThe Netherlands

Background:Mitochondrial dysfunction plays a prominent role in the pathogenesis of Parkinson’s disease(PD),and several genes linked to familial PD,including PINK1(encoding PTEN-induced putative kinase 1[PINK1])and PARK2(encoding the E3 ubiquitin ligase Parkin),are directly involved in processes such as mitophagy that maintain mitochondrial health.The dominant p.D620N variant of vacuolar protein sorting 35 ortholog(VPS35)gene is also associated with familial PD but has not been functionally connected to PINK1 and PARK2.Methods:To better mimic and study the patient situation,we used CRISPR-Cas9 to generate heterozygous human SH-SY5Y cells carrying the PD-associated D620N variant of VPS35.These cells were treated with a protonophore carbonyl cyanide m-chlorophenylhydrazone(CCCP)to induce the PINK1/Parkin-mediated mitophagy,which was assessed using biochemical and microscopy approaches.Results:Mitochondria in the VPS35-D620N cells exhibited reduced mitochondrial membrane potential and appeared to already be damaged at steady state.As a result,the mitochondria of these cells were desensitized to the CCCPinduced collapse in mitochondrial potential,as they displayed altered fragmentation and were unable to accumulate PINK1 at their surface upon this insult.Consequently,Parkin recruitment to the cell surface was inhibited and initiation of the PINK1/Parkin-dependent mitophagy was impaired.Conclusion:Our findings extend the pool of evidence that the p.D620N mutation of VPS35 causes mitochondrial dysfunction and suggest a converging pathogenic mechanism among VPS35,PINK1 and Parkin in PD.

关键词： VPS35 PINK1 Parkin Mitophagy Mitochondrial membrane potential Parkinson’s disease

糖尿病肾病合并上尿路感染患者PINK1/Parkin mRNA与mAlb及其诊断价值

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中华医院感染学杂志 2023年第20期33卷 3061-3065页

作者：魏冉彭丽梁芳李素荣王晶郑领涛石振峰张军英卢懿邢台市人民医院内分泌实验室河北邢台054001 邢台市人民医院内分泌科河北邢台054001 邢台市人民医院疼痛科河北邢台054001 邢台市人民医院肾脏内科河北邢台054001

目的分析糖尿病肾病(DN)合并上尿路感染患者PINK1/Parkin mRNA与尿微量白蛋白(mAlb)的关系。方法选择2019年10月-2020年9月邢台市人民医院收治的DN合并上尿路感染患者73例作为研究组,选择同期医院收治的DN未合并上尿路感染患者141例作... 详细信息

目的分析糖尿病肾病(DN)合并上尿路感染患者PINK1/Parkin mRNA与尿微量白蛋白(mAlb)的关系。方法选择2019年10月-2020年9月邢台市人民医院收治的DN合并上尿路感染患者73例作为研究组,选择同期医院收治的DN未合并上尿路感染患者141例作为对照组;依据糖尿病肾脏疾病肾小管间质和血管损害病理评分(RPS)将73例DN合并上尿路感染患者按照肾小管间质及血管受损程度分为轻度组(n=15)、中度组(n=28)和重度组(n=30);通过逆转录聚合酶链式反应(RT-PCR)技术检测上述患者外周血PINK1 mRNA及Parkin mRNA表达量,免疫比浊法检测mAlb,比较上述不同分组患者各指标。结果研究组患者PINK1 mRNA、Parkin mRNA及mAlb均高于对照组(PPINK1 mRNA、Parkin mRNA、mAlb和RPS评分均较轻、中度组升高,中度组较轻度组升高(PPINK1 mRNA、Parkin mRNA及二者预测DN患者合并上尿路感染患者肾功能损伤均有较高效能,其中二者联合诊断效能较高,其约登指数为0.678,曲线下面积(AUC)为0.853;PINK1 mRNA、Parkin mRNA与mAlb水平呈正相关(r=0.668、0.559,P均12、0.478,P均PINK1mRNA、Parkin mRNA及二者联合指导DN合并上尿路感染肾功能损伤轻中度与重度的区分均有较高效能,三者联合诊断时效能最高。结论DN患者合并上尿路感染时PINK1/Parkin通路被激活,外周血单个核细胞的PINK1 mRNA、Parkin mRNA表达量异常升高,且与mAlb及肾功能损伤程度呈正相关,二者联合诊断DN合并上尿路感染患者肾功能损伤的程度具有较高效能。

关键词：糖尿病肾病上尿路感染肾功能损伤 PINK1 Parkin 尿微量白蛋白诊断价值