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Aldehyde Dehydrogenase 1 making molecular inroads into the differential vulnerability of nigrostriatal dopaminergic neuron subtypes in Parkinson’s disease

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Translational Neurodegeneration 2014年第1期3卷 212-218页

作者： Huaibin Cai Guoxiang Liu Lixin Sun Jinhui Ding Transgenics Section Laboratory of NeurogeneticsNational Institute on AgingNational Institutes of HealthBethesdaMD 20892USA Computational Biology Core Laboratory of NeurogeneticsNational Institute on AgingNational Institutes of HealthBethesdaMD 20892USA

A preferential dysfunction/loss of dopaminergic(DA)neurons in the substantia nigra pars compacta(SNpc)accounts for the main motor symptoms of Parkinson’s disease(PD),the most common degenerative movement ***,the neuronal loss is not stochastic,but rather displays regionally selectivity,indicating the existence of different DA subpopulations in the *** identify the underlying molecular determinants is thereby instrumental in understanding the pathophysiological mechanisms of PD-related neuron dysfunction/loss and offering new therapeutic ***,we have demonstrated that aldehyde dehydrogenase 1(ALDH1A1)is one such molecular determinant that defines and protects an SNpc DA neuron subpopulation preferentially affected in *** this review,we provide further analysis and discussion on the roles of ALDH1A1 in the function and survival of SNpc DA neurons in both rodent and human *** also explore the feasibility of ALDH1A1 as a potential biomarker and therapeutic target for PD.

关键词： Parkinson’s disease Substantia nigra pars compacta dopaminergic neuron Aldehyde dehydrogenase 1,α-synuclein Neurodegeneration Aging

NOX4 exacerbates Parkinson's disease pathology by promoting neuronal ferroptosis and neuroinflammation

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Neural Regeneration Research 2025年第7期20卷 2038-2052页

作者： Zhihao Lin Changzhou Ying Xiaoli Si Naijia Xue Yi Liu Ran Zheng Ying Chen Jiali Pu Baorong Zhang Department of Neurology The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina

Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra ***,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic ***,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely *** oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains *** aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what *** found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease *** oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic ***,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model ***,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic ***,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced *** findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.

关键词： dopaminergic neuron ferroptosis NADPH oxidase 4(NOX4) neuroinflammation Parkinson's disease

Stress increases MHC-I expression in dopaminergic neurons and induces autoimmune activation in Parkinson’s disease

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Neural Regeneration Research 2021年第12期16卷 2521-2527页

作者： Bao-Yan Wang Yong-Yi Ye Chen Qian Hong-Bo Zhang Heng-Xu Mao Long-Ping Yao Xiang Sun Guo-Hui Lu Shi-Zhong Zhang The National Key Clinical Specialty The Engineering Technology Research Center of Education Ministry of ChinaGuangdong Provincial Key Laboratory on Brain Function Repair and RegenerationDepartment of NeurosurgeryZhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong ProvinceChina Department of Neurosurgery the Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong ProvinceChina Department of Neurosurgery First Affiliated Hospital of Nanchang UniversityNanchangJiangxi ProvinceChina

The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurrence and development of Parkinson’s ***,it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I *** the present study,polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium(MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease mouse *** findings revealed that MHC-I was expressed in both *** detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells,immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8(CD8)+T cell infiltration in the substantia nigra of MPTP-treated *** results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+T ***,in MPTP-induced Parkinson’s disease model mice,the genetic knockdown of endogenous MHC-I,which was caused by injecting specific adenovirus into the substantia nigra,led to a significant reduction in CD8+T cell infiltration and alleviated dopaminergic neuronal *** further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation,the expression of PTEN-induced kinase 1(PINK1)was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA(siRNA),and there was more presentation of MHC-I in these cells compared with control siRNA-treated *** together,MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation,thus rendering dopaminergic neurons susceptible to immune cells and *** may be one of the mechanisms of oxidative stress-induced Parkinson’s disease,and implies the potential

关键词： antigen presentation autoimmune CD8+T cell dopaminergic neuron major histocompatibility complex class I mitochondria neuroinflammation oxidative stress Parkinson’s disease PINK1

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson’s disease

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Neural Regeneration Research 2008年第9期3卷 1037-1040页

作者： Haixia Ding Meijiang Feng Xinsheng Ding Department of Neurology the First Affiliated Hospital of Nanjing Medical University Nanjing 210029 Jiangsu Province China Department of Gerontology the Second Affiliated Hospital of Nanjing Medical University Nanjing 210029 Jiangsu Province China

Parkinson＇s disease （PD） is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor （BDNF） mRNA （20%） than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.

关键词： brain-derived neurotrophic factor dopaminergic neuron Parkinson's disease

Protective effects of nicotine on gamma-aminobutyricacid neurons and dopaminergic neurons in micewith Parkinson disease

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Frontiers of Medicine 2009年第3期3卷 330-335页

作者： Lei FU Yue LI Dezheng GONG Dengqin YU Jin GONG Yanhui FENG Yan PENG Dongmei WANG Hong XU Shengming YIN Yiping SUN Lab of Physiological Function College of Basic MedicineDalian Medical UniversityDalian 116044China Department of Physiology College of Basic MedicineDalian Medical UniversityDalian 116044China Department of Anatomy College of Basic MedicineDalian Medical UniversityDalian 116044China

This study aimed to investigate the protective effect of nicotine on dopaminergic neurons and its mechanisms in mice with Parkinson disease(PD)induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).C57BL/6J mice were injected with MPTP for 8 days to establish a PD *** was given for 10 days in the nicotine therapeutic *** were examined behaviorally with the pole test and traction *** hydroxylase(TH)andγ-aminobutyric acid(GABA)were determined by using the immunocytochem-istry(ICC)*** ultrastructural changes of the caudate nucleus(CN)were observed under electron *** results showed that pretreatment with nicotine could improve the dyskinesia of PD mice ***,TH-positive(Pneurons and GABA-positive(Pneurons in the nicotine therapeutic group were signiﬁcantly more than those in the model *** ultrastructural injury of the nicotine therapeutic group was also *** has protective effects on theγ-aminobutyric acid neurons and dopaminergic neurons in the MPTP-treated mice.

关键词： Parkinson disease nicotine dopaminergic neuron gamma-aminobutyric acid neuron

SH-SY5Y human neuroblastoma cell line： in vitro cell model of dopaminergic neurons in Parkinson＇s disease

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Chinese Medical Journal 2010年第8期123卷 1086-1092页

作者： XIE Hong-rong HU Lin-sen LI Guo-yi Department of Neurology the First Hospital Jilin University Changchun 130021 China

Objective To evaluate the human neuroblastoma SH-SY5Y cell line as an in vitro model of dopaminergic （DAergic） neurons for Parkinson＇s disease （PD） research and to determine the effect of differentiation on this cell model. Date sources The data of this review were selected from the original reports and reviews related to SH-SY5Y cells published in Chinese and foreign journals （Pubmed 1973 to 2009）. Study selection After searching the literature, 60 articles were selected to address this review. Results The SH-SY5Y cell line has become a popular cell model for PD research because this cell line posses many characteristics of DAergic neurons. For example, these cells express tyrosine hydroxylase and dopamine-13-hydroxylase, as well as the dopamine transporter. Moreover, this cell line can be differentiated into a functionally mature neuronal phenotype in the presence of various agents. Upon differentiation, SH-SY5Y cells stop proliferating and a constant cell number is subsequently maintained. However, different differentiating agents induce different neuronal phenotypes and biochemical changes. For example, retinoic acid induces differentiation toward a cholinergic neuronal phenotype and increases the susceptibility of SH-SY5Y cells to neurotoxins and neuroprotective agents, whereas treatment with retinoic acid followed by phorbol ester 12-O-tetradecanoylphorbol-13-acetate results in a DAergic neuronal phenotype and decreases the susceptibility of cells to neurotoxins and neuroprotective agents. Some differentiating agents also alter kinetics of 1-methyl-4-phenyl-pyridinium （MPP~） uptake, making SH-SY5Y cells more similar to primary mesencephalic neurons. Conclusions Differentiated and undifferentiated SH-SY5Y cells have been widely used as a cell model of DAergic neurons for PD research. Some differentiating agents afford SH-SY5Y cells with more potential for studying neurotoxiclty and neuroprotection and are thus more relevant to experimental PD research.

关键词： Parkinson's disease SH-SY5Y cells cell model differentiation dopaminergic neuron

Modulation of the activity of dopaminergic neurons by SK channels:a potential target for the treatment of Parkinson's disease?

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Neuroscience Bulletin 2010年第3期26卷 265-271页

作者：刘小坤王刚陈生弟上海交通大学医学院附属瑞金医院神经内科上海交通大学医学院神经病学研究所上海交通大学医学院/中国科学院上海生命科学研究院健康科学研究所神经变性疾病实验室上海200025

SK channels are small conductance calcium-activated potassium channels that are widely expressed in different neurons with distinct *** play an important role in modulating synaptic plasticity,dopaminergic neurotransmission, and learning and *** present review was mainly focused on the recent findings on the contradictory roles of SK channels in modulating dopaminergic neurons in substantia nigra and in the pathogenesis of Parkinson＇s disease （PD） . Besides,whether modulation of SK channels could be a potential target for PD treatment was also discussed.

关键词： small-conductance calcium-activated potassium channel Parkinson's disease afterhyperpolarization dopaminergic neuron

Thrombin-induced microglial activation contributes to the degeneration of nigral dopaminergic neurons in vivo

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Neuroscience Bulletin 2008年第2期24卷 66-72页

作者：黄承芳黎钢马嵘孙圣刚陈建国华中科技大学同济医学院附属协和医院神经内科武汉4300222 华中科技大学同济医学院药理学系武汉430022

Objective To evaluate the role of thrombin-activated microglia in the neurodegeneration of nigral dopaminergic neurons in the rat substantia nigra （SN） in vivo. Methods After stereotaxic thrombin injection into unilateral SN of rats, immunostaining, reverse transcription polymerase chain reaction （RT-PCR） and biochemical methods were used to observe tyrosine hydroxylase （TH） irnmunoreactive positive cells, microglia activation, nitric oxide （NO） amount and inducible nitricoxide synthase （iNOS） expression. Results （1） Selective damage to dopaminergic neurons was produced after thrombin injection, which was evidenced by loss of TH imrnunostaining in time-dependent manner; （2） Strong microglial activation was observed in the SN; （3） RT-PCR demonstrated the early and transient expression of neurotoxic factors iNOS mRNA in the SN. Immunofluorescence results found that thrombin induced expression of iNOS in microglia. The NO production in the thrombininjected rats was significantly higher than that of controls （P 〈 0.05）. Conclusion Thrombin intranigral injection can injure the dopaminergic neurons in the SN. Thrombin-induced microglia activation precedes dopaminergic neuron degeneration, which suggest that activation of microglia and release of NO may play important roles in dopaminergic neuronal death in the SN.

关键词： thrombin dopaminergic neuron microglia Parkinson's disease NO

A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease

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Neural Regeneration Research 2024年第8期19卷 1828-1834页

作者： Yongjiang Zhang Shiyi Yin Run Song Xiaoyi Lai Mengmeng Shen Jiannan Wu Junqiang Yan Key Laboratory of Neuromolecular Biology The First Affiliated HospitalCollege of Clinical Medicine of Henan University of Science and TechnologyLuoyangHenan ProvinceChina Department of Neurology The First Affiliated HospitalCollege of Clinical Medicine of Henan University of Science and TechnologyLuoyangHenan ProvinceChina

Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains ***-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains *** kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum *** is regulated by PERK and is a target of the unfolded protein *** is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh *** this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s *** used adeno-associated virus to knockdown PHB2 *** res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s *** rexpression of PHB2 inhibited these *** also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s *** found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted *** addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of *** findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.

关键词： endoplasmic reticulum dopaminergic neuron microtubule-associated protein 1 light chain 3 mitophagy oxidative stress Parkin Parkinson’s disease PKR-like endoplasmic reticulum kinase reactive oxygen species prohibitin-2