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A core-satellite-like nanoassembly reverses a decisive tyrosine hydroxylase loss in degenerative dopaminergic neurons

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Nano Research 2023年第7期16卷 9835-9847页

作者： Ke Yao Jiamin Gan Di Zhao Mingding Li Xiaoquan Shen Yumin Yang Peijian Feng Qundong Shen Department of Polymer Science&Engineering and Key Laboratory of High-Performance Polymer Materials and Technology of MOE School of Chemistry&Chemical EngineeringNanjing UniversityNanjing 210023China Key Laboratory for Neuroregeneration of Jiangsu Province and Ministry of Education Co-innovation Center of NeuroregenerationNantong UniversityNantong 226001China Medical School of Nanjing University Nanjing 210008China State Key Laboratory of Analytical Chemistry for Life Science Nanjing UniversityNanjing 210023China

In recent years,neurodegenerative diseases,such as Parkinson’s or Alzheimer’s diseases,are rapidly rising in prevalence.The main hallmark of Parkinson’s disease is the falling levels of neurotransmitter dopamine in the mid-brain with dopaminergic neurons losing.Typical therapeutic solutions,including drugs,deep brain stimulation,and cell transplantation,can only alleviate the symptoms of Parkinson’s disease.It is a tremendous challenge to reverse the function degeneration of the crucial dopaminergic neurons.Herein,we develop a core-satellite-like nanoassembly(PDA-AFn(by integrating polydopamine nanoparticles and apoferritin))to raise the expression of tyrosine hydroxylase(TH),a rate-limiting enzyme in the formation of the dopamine.Both components in the nanoassembly could cooperate with each other,not only elaborately regulate the iron homeostasis and redox microenvironment,but also utilize excessive reactive oxygen species(ROS)and iron ions in the damaged neurons to supply extra dopamine and enhance TH activity,and consequently restore the function of the degenerated neurons.Remarkably,the nanoassembly-treatment relieves the dyskinesia and dramatical increases the tyrosine hydroxylase and dopamine level in the midbrain of Parkinson’s disease model mice.It is an explicit yet inspiring advance in treatment of the neurodegeneration.

关键词： neurodegenerative disease dopaminergic neurons tyrosine hydroxylase apoferritin Parkinson’s disease

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tyrosine hydroxylase as a Target for Deltamethrin in the Nigrostriatal Dopaminergic Pathway

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Biomedical and Environmental Sciences 2006年第1期19卷 27-34页

作者： GONG-PING LIU QIANG MA NIAN SHI Department of Toxicology MOE key Laboratory of Environmental and Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 Hubei China Receptor Biology Laboratory Toxicology and Molecular Biology Branch Health Effects Laboratory Division National Institute for Occupational Safety and Health Centers for Disease Control and Prevention Morgantown WV 26505 USA

Objective To study the effects of deltamethrin on tyrosine hydroxylase in nigrostriatum of male rats. Methods Sprague-Dawley rats were daily treated with deltamethrin at 6.25 or 12.5 mg/kg body weight by gavage for 10 days. Then HPLC-fluorescence detection was used to analyze the contents of dopamine （DA）, 3,4-dihydmxyphenylacetic acid （DOPAC） and homoranillic acid （HVA） in substantial nigra and striatum. The activities of tyrosine hydroxylase （TH） were also detected by HPLC-fluorescence detection. TH mRNA or TH protein levels were measured by RT-PCR and immunohistochemistry method. Results The content of DA in stfiatum was significantly decreased by the treatments, suggesting an inhibition of DA synthesis by deltamethrin. The contents of DA metabolites DOPAC and HVA increased, indicating increased dopamine turnover. Furthermore, deltamethrin significantly decreased the activity, as well as the mRNA and protein levels of TH. Conclusions These findings reveal a novel aspect of deltamethfin neurotoxicity and suggest tyrosine hydroxylase as a molecular target of deltamethin on dopamine metabolism in the nigrostriatal pathway.

关键词： Deltamethrin Nigrostriatum Dopamine tyrosine hydroxylase Parkinson＇s disease

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tyrosine hydroxylase expression in the midbrain of Parkinson's disease model rats treated with Xifeng Dingchan decoction

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Neural Regeneration Research 2011年第12期6卷 914-918页

作者： Enli Luo First Department of Neurology the Second Clinical Medical College Guangzhou University of Traditional Chinese Medicine Guangzhou 510120 Guangdong Province China Post-doctoral Research Station Guangzhou University of Traditional Chinese Medicine Guangzhou 510006 Guangdong Province China

This study showed that abnormal behavioral changes were greatly improved in rats displaying Parkinson＇s disease-like symptoms after intragastric administration of Xifeng Dingchan decoction at 15, 7.5, 3.75 g/kg per day. In addition, tyrosine hydroxylase mRNA expression in the substantia nigra of the midbrain was up-regulated, and tyrosine hydroxylase content in the midbrain ventral tegmentum and substantia nigra pars compacta was also increased. The effect of administration of Xifeng Dingchan decoction at 7.5 g/kg per day was similar to that of Madopar at 67.5 mg/kg per day. These results indicate that the therapeutic effect of Xifeng Dingchan decoction on Parkinson＇s disease is associated with the up-regulated protein and mRNA expression of tyrosine hydroxylase in the midbrain.

关键词： Parkinson＇s disease Xifeng Dingchan decoction tyrosine hydroxylase midbrain behavior Chinese herbal medicine neural regeneration

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Dark rearing maintains tyrosine hydroxylase expression in retinal amacrine cells following optic nerve transection

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Neural Regeneration Research 2012年第1期7卷 18-23页

作者： Wei Wan Zhenghai Liu Xiaosheng Wang Xuegang Luo Department of Human Anatomy and Neurobiology Xiangya Medical College of Central South University Changsha 410013 Hunan Province China Department of Human Anatomy University of South China Hengyang 421001 Hunan Province China

The present study examined changes in retinal tyrosine hydroxylase （TH） expression in rats having undergone optic nerve transection and housed under a normal day/night cycle or in the dark. The aim was to investigate the effects of amacrine cells on axonal regeneration in retinal ganglion cells and on the synapses that transmit visual signals. The results revealed that retinal TH expression gradually decreased following optic nerve transection in rats housed under a normal day/night cycle reaching a minimum at 5 days. In contrast, retinal TH expression decreased to a minimum at 1 day following optic nerve transection in dark reared rats, gradually increasing afterward and reaching a normal level at 5 7 days. The number of TH-positive synaptic particles correlated with the TH levels indicating that dark rearing can help maintain TH expression during the synaptic degeneration stage （5 7 days after optic nerve injury） in retinal amacrine cells.

关键词： optic nerve transection tyrosine hydroxylase dark rearing amacrine cells peripheral nerve injury neural regeneration

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CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson's disease

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Neural Regeneration Research 2024年第1期19卷 196-204页

作者： Xiang Chen Yuwan Lin Zhiling Zhang Yuting Tang Panghai Ye Wei Dai Wenlong Zhang Hanqun Liu Guoyou Peng Shuxuan Huang Jiewen Qiu Wenyuan Guo Xiaoqin Zhu Zhuohua Wu Yaoyun Kuang Pingyi Xu Miaomiao Zhou Department of Neurology The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong ProvinceChina Department of Neurology The People’s Hospital of Guangxi Zhuang Autonomous RegionNanningGuangxi Zhuang Autonomous RegionChina School of Basic Medical Sciences Guangzhou Medical UniversityGuangzhouGuangdong ProvinceChina Department of Neurology Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucial mitochondrial protein,has been reported to cause Parkinson's disease.FIFO-ATPase participates in the synthesis of cellular adenosine triphosphate(ATP)and plays a central role in mitochondrial energy metabolism.However,the specific roles of wild-type(WT)CHCHD2 and T611-mutant CHCHD2 in regulating F1FO-ATPase activity in Parkinson's disease,as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1FO-ATPase activity,remain unclea r.Therefore,in this study,we expressed WT CHCHD2 and T61l-mutant CHCHD2 in an MPP^(+)-induced SH-SY5Y cell model of PD.We found that CHCHD2 protected mitochondria from developing MPP^(+)-induced dysfunction.Under normal conditions,ove rexpression of WT CHCHD2 promoted F1FO-ATPase assembly,while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1FO-ATPase assembly.In addition,mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1FO-ATPase.Three weeks after transfection with AAV-CHCHD2 T61I,we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model.These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.

关键词： ATP synthase(F1F0-ATPase) coiled-coil helix coiled-coil helix domain containing 2 dopaminergic neuron mitochondrial dysfunction neurodegeneration oligomycin sensitivity-conferring protein Parkinson's disease T61I mutation tyrosine hydroxylase

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Treatment time influences the effects of a low-frequency pulsed electric field on synthesis of tyrosine hydroxylase and dopamine in PC12 cells

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Neural Regeneration Research 2010年第4期5卷 291-294页

作者： Hongfeng Zhang Yuanzhang Fang Ying Liu Hongxing Qi School of Life Science East China Normal University Shanghai 200062 China Key Laboratory of Optical and Magnetic Resonance Spectroscopy Department of Physics East China Normal University Shanghai 200062 China

BACKGROUND： Electromagnetic radiation can influence dopamine （DA） synthesis in brain tissues or ceils, but electromagnetic frequencies, intensities, and radiation time can produce different effects. In addition, the signal pathway by which electromagnetic radiation influences DA synthesis remains controversial. OBJECTIVE： To determine tyrosine hydroxylase （TH） expression in PC12 cells and DA levels in cell culture media after different periods of low-frequency pulsed electric field （LF-PEF） stimulation, and to determine how LF-PEF signaling stimulates TH synthesis using inhibitors. DESIGN, TIME AND SETTING： A parallel, controlled, cell experiment was performed at the Laboratory of Cell Biology, School of Life Science, East China Normal University, between January and October 2006. MATERIALS： PC12 cells were purchased from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, China. Nerve growth factor was purchased from PeproTech, USA. The protein kinase A inhibitor, H-89, and mitogen-activated protein kinase kinase inhibitor, U0126, were purchased from Sigma, USA. METHODS：（1） Following routine culture in Dulbecco＇s modified eagle medium, primary PC12 cells were stimulated under LF-PEF （pulse frequency 50.Hz, pulse width 20 μs, peak field strength 1 V/m） for 5, 10, 15, 20, and 30 minutes. （2） Inhibitors （H-89 or U0126, 1 μmol/L） were added 30 minutes before LF-PEF stimulation for 10 minutes. MAIN OUTCOME MEASURES：（1） TH expression was determined by Western blot in PC12 cells at 0.5, 1,2, 3, and 4 days after LF-PEF stimulation. Similarly, DA was measured by high-performance liquid chromatography in media at 2, 3, 4, or 5 days after LF-PEE （2） TH expression was detected 1 day after H-89 or U0126 treatment and LF-PEE RESULTS：（1） Short-term LF-PEF stimulation （5 and 10 minutes） increased TH expression and media DA levels after short-term culture （2 days）（P 〈 0.01）, but both parameters decreased with longer culture （3 4 days）（P 〈 0.01）. Long-term LF-PEF stimulation （15, 20, or 30 m

关键词： low-frequency pulsed electric field PC12 cells tyrosine hydroxylase dopamine protein kinase A pathway Ras/mitogen-activated protein kinase kinase 1/2 pathway

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tyrosine hydroxylase gene transfections to different sites of striatum in the rat model of Parkinson’s disease

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Open Journal of Genetics 2013年第2期3卷 30-37页

作者： Atso Raasmaja Sarka Lehtonen Tiina Kaariainen Pasi Lampela Marko Huotari Anne Lecklin Division of Pharmacology&Toxicology University of HelsinkiHelsinkiFinland Department of Pharmacy University of Eastern FinlandKuopioFinland

The use of gene therapy has been intensively studied as a potential method to treat Parkinson’s disease (PD) and other degenerative brain diseases. However, the effects of experimental measures and approaches on the outcome of gene delivery or on the physiological state of target tissues have not been analyzed as much and systematically. Therefore, we have infused adenovirus vectors expressing either a therapeutic tyrosine hydroxylase (TH) gene or a lacZ reporter gene into striatum in a rat model of PD. The experimental procedures were tested using the Ad lacZ vector in order to optimize concentrations, volumes, infusion speeds and transfection times. The expression of Ad lacZ vector was lower and declined earlier in the lesioned than unlesioned striatum suggesting that the lesion affects on the transfection efficiency and outcome of gene transfection. The effect of three different approaches of Ad TH vector transfection was compared: 1) the delivery of Ad TH gene vector alone into one single site of striatum, 2) the delivery of Ad TH gene vector alone into multiple sites of striatum, and 3) the delivery of Ad TH gene vector into one site of striatum followed by a continuous infusion of tetrahydrobiopterin (BH4) cofactor with a mini pump. There was a small and transient unsignificant decrease in the turning behavior when the Ad TH vector was delivered into one site of the striatum. Simultaneous infusion into several sites or together with BH4 cofactor did not improve more the effect of gene delivery. Thus, although the effects were unsignificant, the Ad TH transfection seemed to decrease the turning behavior in the rat model of PD and the optimal effect was seen at some specific doses and time points. Furthermore, the outcome of gene therapy could depend in addition to the amount and efficacy of gene vectors also on the physiological state and experimental strategies.

关键词： tyrosine hydroxylase Tetrahydrobiopterin Adenovirus Vector 6-Hydroxydopamine Parkinson’s Disease Gene Therapy

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Effect of Bushen Huoxue Decoction(补肾活血饮) on the Orphan Receptor and tyrosine hydroxylase in the Brain of Rats with Parkinson's Disease

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Chinese Journal of Integrative Medicine 2011年第1期17卷 43-47页

作者：杨明会王海明刘毅 Institute of Traditional Chinese Medicine General Hospital of PLA

Objective：To explore the effect of Bushen Huoxue Decoction（补肾活血饮,BHD） on the orphan receptor（Nurr1） and tyrosine hydroxylase（TH） in the brain of rats with Parkinson＇s disease（PD）.Methods：One hundred and twenty SD rats were divided into 100 in the model group and 20 in the normal control group,fifty-eight SD rats from the model group,established into PD model successfully by injuring their substantia nigra （SSN） with 6-hydroxydopamine,were divided equally into the model group and the test group,and they were treated with saline and BHD,respectively,for eight successive weeks.The change in the rats＇ behavior before and after treatment was observed by counting the cycles of rotation induced by apomorphine injection; the pathology of neurons,level of Nurr1 mRNA expression,and amount of TH positive cells in SSN were observed after treatment.Results：The rats＇ behavior was improved in the tested group significantly,the rotation cycle after treatment being 84.0±20.0 cycles/40 min,which was significantly lower than that in the model group（377.0±62.3 cycles/40 min,P〈0.01）.Besides,the Nurr1 mRNA expression and TH positive cell in the test group were 0.97±0.15 and 49.40±14.72,respectively,which were significantly higher than those in the model group,0.22±0.03 and 5.45±2.58,respectively（all P〈0.01）.Conclusion：BHD could treat PD by enhancing the Nurr1 mRNA expression,increasing the TH content in brain,and promoting the repairing of injured neuron in cerebral SSN.

关键词： Parkinson＇s disease Bushen Huoxue Decoction Chinese medicine Orphan receptor tyrosine hydroxylase

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Melanin synthesis genes BgTH and BgDdc affect body color and cuticle permeability in Blattella germanica

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Insect Science 2022年第6期29卷 1552-1568页

作者： Tian-Tian Bai Xiao-Jin Pei Tong-Xian Liu Yong-Liang Fan Shi-Ze Zhang State Key Laboratory of Crop Stress Biology for Arid Areas and Key Laboratory of lIntegrated Pest Management on Crops in Northwestern Loess Plateau Ministry of AgricultureNorthwest A&F UniversityYanglingShaanxiChina Present address:Guangdong Provincial Key Laboratory of Insect Developmental Biology and Applied Technology and Institute of Insect Science and Technology School of Life SciencesSouth China Normal UniversityGuangzhou510631China

Melanin is involved in cuticle pigmentation and sclerotization of insects,which is critical for maintaining structural integrity and functional completeness of insect cuti-cle.The 2 key enzymes of tyrosine hydroxylase(TH)and dopa decarboxylase(DDC)predicted in melanin biosynthesis are usually conserved in insects.However,it is unclear whether their function is related to epidermal permeability.In this study,we identified and cloned the gene sequences of BgTH and BgDdc from Blattella germanica,and revealed that they both showed a high expression at the molting,and BgTH was abundant in the head and integument while BgDdc was expressed highest in the fat body.Using RNA in-terference(RNAi),we found that knockdown of BgTH caused molting obstacles in some cockroaches,with the survivors showing pale color and softer integuments,while knock-down of BgDdc was viable and generated an abnormal light brown body color.Desiccation assay showed that the dsBgTH-injected adults died earlier than control groups under a dry atmosphere,but dsBgDdc-injected cockroaches did not.In contrast,when dsRNA-treated cockroaches were reared under a high humidity condition,almost no cockroaches died in all treatments.Furthermore,with eosin Y staining assay,we found that BgTH-RNAi resulted in a higher cuticular permeability,and BgDdc-RNAi also caused slight dye pen-etration.These results demonstrate that BgTH and BgDdc function in body pigmentation and affect the waterproofing ability of the cuticle,and the reduction of cuticular perme-ability may be achieved through cuticle melanization.

关键词： cuticular permeability desiccation tolerance dopa decarboxylase German cockroach pigmentation tyrosine hydroxylase

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Single-nuclei RNA sequencing uncovers heterogenous transcriptional signatures in Parkinson's disease associated with nuclear receptor-related factor 1 defect

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Neural Regeneration Research 2023年第9期18卷 2037-2046页

作者： Piniel Alphayo Kambey Wen-Ya Liu Jiao Wu Bakwatanisa Bosco Iqra Nadeem Kouminin Kanwore Dian-Shuai Gao Xuzhou Key Laboratory of Neurobiology Department of Neurobiology and AnatomyXuzhou Medical UniversityXuzhouJiangsu ProvinceChina Organization of African Academic Doctors NairobiKenya Department of Bioinformatics Nanjing Medical UniversityNanjingJiangsu ProvinceChina

Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.

关键词： 6-hydroxydopamine dopaminergic neurons dopamine transporter nuclear receptor-related factor 1 Parkinson’s disease proteomics analysis Seurat clustering single-nuclei RNA sequencing substantia nigra tyrosine hydroxylase

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