28 results on '"Junbing Wu"'
Search Results
2. Connectivity and Functionality of the Globus Pallidus Externa Under Normal Conditions and Parkinson's Disease
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Jie Dong, Sarah Hawes, Junbing Wu, Weidong Le, and Huaibin Cai
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globus pallidus externa ,Parkinson's disease ,basal ganglia ,prototypic neurons ,arkypallidal neurons ,dopaminergic neurons ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The globus pallidus externa (GPe) functions as a central hub in the basal ganglia for processing motor and non-motor information through the creation of complex connections with the other basal ganglia nuclei and brain regions. Recently, with the adoption of sophisticated genetic tools, substantial advances have been made in understanding the distinct molecular, anatomical, electrophysiological, and functional properties of GPe neurons and non-neuronal cells. Impairments in dopamine transmission in the basal ganglia contribute to Parkinson's disease (PD), the most common movement disorder that severely affects the patients' life quality. Altered GPe neuron activity and synaptic connections have also been found in both PD patients and pre-clinical models. In this review, we will summarize the main findings on the composition, connectivity and functionality of different GPe cell populations and the potential GPe-related mechanisms of PD symptoms to better understand the cell type and circuit-specific roles of GPe in both normal and PD conditions.
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- 2021
- Full Text
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3. Aldehyde dehydrogenase 1–positive nigrostriatal dopaminergic fibers exhibit distinct projection pattern and dopamine release dynamics at mouse dorsal striatum
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Carmelo Sgobio, Junbing Wu, Wang Zheng, Xi Chen, Jing Pan, Armando G. Salinas, Margaret I. Davis, David M. Lovinger, and Huaibin Cai
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Medicine ,Science - Abstract
Abstract Aldehyde dehydrogenase 1 (ALDH1A1)–positive dopaminergic (DA) neurons at the ventral substantia nigra pars compacta (SNpc) preferentially degenerate in Parkinson’s disease (PD). Their projection pattern and dopamine release properties, however, remains uncharacterized. Here we show that ALDH1A1–positive axons project predominantly to the rostral two–thirds of dorsal striatum. A portion of these axons converge on a small fraction of striosome compartments restricted to the dorsolateral striatum (DLS), where less dopamine release was measured compared to the adjacent matrix enriched with the ALDH1A1–negative axons. Genetic ablation of Aldh1a1 substantially increases the dopamine release in striosomes, but not in matrix. Additionally, the presence of PD-related human α-synuclein A53T mutant or dopamine transporter (DAT) blockers also differentially affects the dopamine output in striosomes and matrix. Together, these results demonstrate distinct dopamine release characteristics of ALDH1A1–positive DA fibers, supporting a regional specific function of ALDH1A1 in regulating dopamine availability/release in striatum.
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- 2017
- Full Text
- View/download PDF
4. Distinct Connectivity and Functionality of Aldehyde Dehydrogenase 1a1-Positive Nigrostriatal Dopaminergic Neurons in Motor Learning
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Junbing Wu, Justin Kung, Jie Dong, Lisa Chang, Chengsong Xie, Ahsan Habib, Sarah Hawes, Nannan Yang, Vivian Chen, Zhenhua Liu, Rebekah Evans, Bo Liang, Lixin Sun, Jinhui Ding, Jia Yu, Sara Saez-Atienzar, Beisha Tang, Zayd Khaliq, Da-Ting Lin, Weidong Le, and Huaibin Cai
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Biology (General) ,QH301-705.5 - Abstract
Summary: Parkinson’s disease causes the most profound loss of the aldehyde dehydrogenase 1A1-positive (ALDH1A1+) nigrostriatal dopaminergic neuron (nDAN) subpopulation. The connectivity and functionality of ALDH1A1+ nDANs, however, remain poorly understood. Here, we show in rodent brains that ALDH1A1+ nDANs project predominantly to the rostral dorsal striatum, from which they also receive most monosynaptic inputs, indicating extensive reciprocal innervations with the striatal spiny projection neurons (SPNs). Functionally, genetic ablation of ALDH1A1+ nDANs causes severe impairments in motor skill learning, along with a reduction in high-speed walking. While dopamine replacement therapy accelerated walking speed, it failed to improve motor skill learning in ALDH1A1+ nDAN-ablated mice. Altogether, our study provides a comprehensive whole-brain connectivity map and reveals a key physiological function of ALDH1A1+ nDANs in motor skill acquisition, suggesting the motor learning processes require ALDH1A1+ nDANs to integrate diverse presynaptic inputs and supply dopamine with dynamic precision. : Wu et al. show that aldehyde dehydrogenase 1A1-positive nigrostriatal dopaminergic neurons, which display the most profound degeneration in Parkinson’s disease, are essential in the acquisition of skilled movements in rodent models. The proper synaptic inputs to these neurons are critical for providing the timely dopamine release required in the learning process. Keywords: aldehyde dehydrogenase 1a1, ALDH1A1, Parkinson’s disease, dopamine, dopaminergic neurons, substantia nigra, striatum, brain mapping, motor skill learning
- Published
- 2019
- Full Text
- View/download PDF
5. Regulation of neuronal cell death by c-Abl-Hippo/MST2 signaling pathway.
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Weizhe Liu, Junbing Wu, Lei Xiao, Yujie Bai, Aiqin Qu, Zheng Zheng, and Zengqiang Yuan
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Medicine ,Science - Abstract
BACKGROUND: Mammalian Ste20-like kinases (MSTs) are the mammalian homologue of Drosophila hippo and play critical roles in regulation of cell death, organ size control, proliferation and tumorigenesis. MSTs exert pro-apoptotic function through cleavage, autophosphorylation and in turn phosphorylation of downstream targets, such as Histone H2B and FOXO (Forkhead box O). Previously we reported that protein kinase c-Abl mediates oxidative stress-induced neuronal cell death through phosphorylating MST1 at Y433, which is not conserved among mammalian MST2, Drosophila Hippo and C.elegans cst-1/2. METHODOLOGY/PRINCIPAL FINDINGS: Using immunoblotting, in vitro kinase and cell death assay, we demonstrate that c-Abl kinase phosphorylates MST2 at an evolutionarily conserved site, Y81, within the kinase domain. We further show that the phosphorylation of MST2 by c-Abl leads to the disruption of the interaction with Raf-1 proteins and the enhancement of homodimerization of MST2 proteins. It thereby enhances the MST2 activation and induces neuronal cell death. CONCLUSIONS/SIGNIFICANCE: The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST2 suggests that the conserved c-Abl-MST signaling cascade plays an important role in oxidative stress-induced neuronal cell death.
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- 2012
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6. Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, striatal dopamine in mice.
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Nasello, Cara, Poppi, Lauren A., Junbing Wu, Kowalski, Tess F., Thackray, Joshua K., Wang, Riley, Persaud, Angelina, Mahboob, Mariam, Lin, Sherry, Spaseska, Rodna, Johnson, C. K., Gordon, Derek, Tissir, Fadel, Heiman, Gary A., Tischfield, Jay A., Bocarsly, Miriam, and Tischfield, Max A.
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REWARD (Psychology) ,TOURETTE syndrome ,REINFORCEMENT (Psychology) ,NEURAL inhibition ,DOPAMINE ,GENETIC counseling - Abstract
Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
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7. Planar cell polarity and the pathogenesis of Tourette Disorder: New hypotheses and perspectives
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Junbing Wu, Lauren A. Poppi, and Max A. Tischfield
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Adult ,Cell Polarity ,Receptors, Cell Surface ,Cell Biology ,Cadherins ,Mice ,Thalamus ,Animals ,Humans ,Neural Tube Defects ,Neurulation ,Molecular Biology ,Tourette Syndrome ,Developmental Biology - Abstract
Planar cell polarity (PCP) signaling plays a fundamental role in shaping the development and ongoing function of the nervous system, beginning from early stages of neural tube closure and spanning the maintenance of functional synapses in adults. While mutations in core PCP signaling proteins have long been suspected to underlie neural tube closure defects in humans, recent findings also implicate their potential involvement in neurodevelopmental and neuropsychiatric disorders. Missense and loss-of-function mutations in CELSR3, a core component of PCP signaling complexes, are highly associated with Tourette Disorder. Although the functional significance of these mutations has yet to be elucidated in animal and cell models, the expression patterns of Celsr3 in mice point to alterations in cortico-striato-thalamo-cortical circuits. Here, we briefly review the known functions of Celsr3 for nervous system development. We also propose circuit models for Tourette Disorder by hypothesizing roles for Celsr3 in controlling striatal neuromodulation via effects on cholinergic interneurons, and thalamic inhibition through its functions in thalamic reticular nuclei. Testing these and related hypotheses in animal and cell models will move us closer to unraveling the neuropathogenesis of Tourette Disorder, with the ultimate goal of developing more efficacious treatments for both motor and cognitive symptoms.
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- 2022
8. A cadherin mutation in Celsr3 linked to Tourette Disorder affects dendritic patterning and excitability of cholinergic interneurons
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Lauren A. Poppi, K.T. Ho-Nguyen, Junbing Wu, Matthew Matrongolo, Joshua K. Thackray, Cara Nasello, Anna Shi, Matthew Ricci, Nicolas L. Carayannopoulos, Nithisha Cheedalla, Julianne McGinnis, Samantha Schaper, Cynthia Daut, Jurdiana Hernandez, Gary A. Heiman, Jay A. Tischfield, and Max A. Tischfield
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nervous system - Abstract
CELSR3 encodes an atypical protocadherin cell adhesion receptor that was recently identified as a high-risk gene for Tourette disorder. A putative damaging de novo variant was inserted into the mouse genome to generate an amino acid substitution within the fifth cadherin repeat. By contrast to Celsr3 constitutive null animals, mice homozygous for the R774H amino acid substitution are viable and have grossly normal forebrain development. The density of cortical and striatal interneuron subpopulations is normal, but 3D geometric analysis of cortical pyramidal neurons and striatal cholinergic interneurons revealed changes to dendritic patterning and types and distributions of spines. Furthermore, patch clamp recordings in cholinergic interneurons located within the sensorimotor striatum uncovered mild intrinsic hyperexcitability. Despite these changes, Celsr3R774H homozygous mice do not show obvious ‘tic-like’ stereotypies at baseline nor motor learning impairments, but females exhibited perseverative digging behavior. Our findings show that a human mutation in CELSR3 linked to Tourette disorder is sufficient to alter dendritic patterning in the cortex and striatum and also the intrinsic excitability of cholinergic interneurons.
- Published
- 2022
9. Deficiency in endocannabinoid synthase DAGLB contributes to Parkinson’s disease and dopaminergic neuron dysfunction
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Zhenhua Liu, Nannan Yang, Jie Dong, Wotu Tian, Lisa Chang, Jinghong Ma, Jifeng Guo, Jieqiong Tan, Ao Dong, Kaikai He, Jingheng Zhou, Resat Cinar, Junbing Wu, Armando Salinas, Lixin Sun, Justin Kung, Chengsong Xie, Braden Oldham, Mantosh Kumar, Sarah Hawes, Jinhui Ding, Lupeng Wang, Tao Wang, Piu Chan, Zhuohua Zhang, Weidong Le, Shengdi Chen, David M. Lovinger, Guohong Cui, Yulong Li, Huaibin Cai, and Beisha Tang
- Abstract
2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid (eCB) in the brain, regulates diverse neural functions. However, whether 2-AG deficiency contributes to Parkinson’s disease (PD) and nigral dopaminergic neurons (DANs) dysfunction is unclear. Diacylglycerol lipase α and β (DAGLA and DAGLB) mediate the biosynthesis of 2-AG. Using homozygosity mapping and whole-exome sequencing, we linked multiple homozygous loss-of-function mutations in DAGLB to a form of early-onset autosomal recessive PD. We then used RNA sequencing and fiber photometry with genetically encoded eCB sensors to demonstrate that DAGLB is the main 2-AG synthase in nigral DANs. Genetic knockdown of Daglb by CRISPR/Cas9 in mouse nigral DANs substantially reduces 2-AG levels in the substantia nigra (SN). The SN 2-AG levels are markedly correlated with the vigor of movement during the acquisition of motor skills, while Daglb-deficiency impairs motor learning. Conversely, pharmacological enhancement of 2-AG levels increases nigral DAN activity and dopamine release and improves motor learning. Together, we demonstrate that DAGLB-deficiency contributes to the etiopathogenesis of PD, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neural activity and dopamine release, and provide preclinical evidence for the beneficial effects of 2-AG augmentation in PD treatment.
- Published
- 2021
10. Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction
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Zhenhua Liu, Nannan Yang, Jie Dong, Wotu Tian, Lisa Chang, Jinghong Ma, Jifeng Guo, Jieqiong Tan, Ao Dong, Kaikai He, Jingheng Zhou, Resat Cinar, Junbing Wu, Armando G. Salinas, Lixin Sun, Mantosh Kumar, Breanna T. Sullivan, Braden B. Oldham, Vanessa Pitz, Mary B. Makarious, Jinhui Ding, Justin Kung, Chengsong Xie, Sarah L. Hawes, Lupeng Wang, Tao Wang, Piu Chan, Zhuohua Zhang, Weidong Le, Shengdi Chen, David M. Lovinger, Cornelis Blauwendraat, Andrew B. Singleton, Guohong Cui, Yulong Li, Huaibin Cai, and Beisha Tang
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Substantia Nigra ,Lipoprotein Lipase ,Mice ,Multidisciplinary ,Parkinsonian Disorders ,Dopamine ,Dopaminergic Neurons ,General Physics and Astronomy ,Animals ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology ,Endocannabinoids - Abstract
Endocannabinoid (eCB), 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase β (DAGLB) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, the SN 2-AG levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb in nigral DANs substantially reduced SN 2-AG levels and impaired locomotor skill learning, particularly the across-session learning. Conversely, pharmacological inhibition of 2-AG degradation increased nigral 2-AG levels, DAN activity and dopamine release and rescued the locomotor skill learning deficits. Together, we demonstrate that DAGLB-deficiency contributes to the pathogenesis of Parkinsonism, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neuronal activity and dopamine release, and suggest potential benefits of 2-AG augmentation in alleviating Parkinsonism.
- Published
- 2021
11. Correction: DJ-1 interacts with RACK1 and protects neurons from oxidative-stress-induced apoptosis
- Author
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Jian-Qing Ding, Jun Ma, Zheng Zheng, Jizhong Lou, Qiang Zhang, Zengqiang Yuan, Junbing Wu, and Rong Wu
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Chemistry ,Apoptosis ,medicine ,Cell Biology ,medicine.disease_cause ,Molecular Biology ,Biochemistry ,Oxidative stress ,Cell biology - Published
- 2020
12. Distinct Connectivity and Functionality of Aldehyde Dehydrogenase 1a1-Positive Nigrostriatal Dopaminergic Neurons in Motor Learning
- Author
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Jie Dong, Huaibin Cai, Jia Yu, Sara Saez-Atienzar, Junbing Wu, Sarah L. Hawes, Zayd M. Khaliq, Vivian Chen, Zhenhua Liu, Weidong Le, Rebekah C. Evans, Da-Ting Lin, Lisa Chang, Lixin Sun, Jinhui Ding, Justin W. Kung, Nannan Yang, Bo Liang, Chengsong Xie, Ahsan Habib, and Beisha Tang
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0301 basic medicine ,Parkinson's disease ,Dopamine ,Substantia nigra ,Mice, Transgenic ,Striatum ,Biology ,Medium spiny neuron ,General Biochemistry, Genetics and Molecular Biology ,Aldehyde Dehydrogenase 1 Family ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Learning ,lcsh:QH301-705.5 ,Motor skill ,Dopaminergic Neurons ,Dopaminergic ,Retinal Dehydrogenase ,medicine.disease ,Corpus Striatum ,Substantia Nigra ,030104 developmental biology ,nervous system ,lcsh:Biology (General) ,Motor learning ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Summary: Parkinson’s disease causes the most profound loss of the aldehyde dehydrogenase 1A1-positive (ALDH1A1+) nigrostriatal dopaminergic neuron (nDAN) subpopulation. The connectivity and functionality of ALDH1A1+ nDANs, however, remain poorly understood. Here, we show in rodent brains that ALDH1A1+ nDANs project predominantly to the rostral dorsal striatum, from which they also receive most monosynaptic inputs, indicating extensive reciprocal innervations with the striatal spiny projection neurons (SPNs). Functionally, genetic ablation of ALDH1A1+ nDANs causes severe impairments in motor skill learning, along with a reduction in high-speed walking. While dopamine replacement therapy accelerated walking speed, it failed to improve motor skill learning in ALDH1A1+ nDAN-ablated mice. Altogether, our study provides a comprehensive whole-brain connectivity map and reveals a key physiological function of ALDH1A1+ nDANs in motor skill acquisition, suggesting the motor learning processes require ALDH1A1+ nDANs to integrate diverse presynaptic inputs and supply dopamine with dynamic precision. : Wu et al. show that aldehyde dehydrogenase 1A1-positive nigrostriatal dopaminergic neurons, which display the most profound degeneration in Parkinson’s disease, are essential in the acquisition of skilled movements in rodent models. The proper synaptic inputs to these neurons are critical for providing the timely dopamine release required in the learning process. Keywords: aldehyde dehydrogenase 1a1, ALDH1A1, Parkinson’s disease, dopamine, dopaminergic neurons, substantia nigra, striatum, brain mapping, motor skill learning
- Published
- 2019
13. ALDH1A1 regulates postsynaptic μ–opioid receptor expression in dorsal striatal projection neurons and mitigates dyskinesia through transsynaptic retinoic acid signaling
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Lisa Chang, Jinhui Ding, Jing Pan, Huaibin Cai, Sarah L. Hawes, Jia Yu, Weidong Le, Chengsong Xie, Sheng-Di Chen, Junbing Wu, Justin W. Kung, Sara Saez–Atienzar, Lixin Sun, and Wang Zheng
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0301 basic medicine ,Male ,medicine.medical_specialty ,medicine.drug_class ,Dopamine ,Retinoic acid ,Receptors, Opioid, mu ,lcsh:Medicine ,Tretinoin ,Striatum ,Biology ,Article ,Aldehyde Dehydrogenase 1 Family ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Postsynaptic potential ,Opioid receptor ,Internal medicine ,Basal ganglia ,medicine ,Animals ,education ,lcsh:Science ,Homeodomain Proteins ,Mice, Knockout ,education.field_of_study ,Multidisciplinary ,Dyskinesias ,Dopaminergic Neurons ,Dopaminergic ,lcsh:R ,Retinal Dehydrogenase ,Corpus Striatum ,030104 developmental biology ,Endocrinology ,chemistry ,nervous system ,Knockout mouse ,Pituitary homeobox 3 ,lcsh:Q ,Female ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Aldehyde dehydrogenase 1A1 (ALDH1A1), a retinoic acid (RA) synthase, is selectively expressed by the nigrostriatal dopaminergic (nDA) neurons that preferentially degenerate in Parkinson’s disease (PD). ALDH1A1–positive axons mainly project to the dorsal striatum. However, whether ALDH1A1 and its products regulate the activity of postsynaptic striatal neurons is unclear. Here we show that μ–type opioid receptor (MOR1) levels were severely decreased in the dorsal striatum of postnatal and adult Aldh1a1 knockout mice, whereas dietary supplement of RA restores its expression. Furthermore, RA treatment also upregulates striatal MOR1 levels and signaling and alleviates L-DOPA–induced dyskinetic movements in pituitary homeobox 3 (Pitx3)–deficient mice that lack of ALDH1A1–expressing nDA neurons. Therefore, our findings demonstrate that ALDH1A1–synthesized RA is required for postsynaptic MOR1 expression in the postnatal and adult dorsal striatum, supporting potential therapeutic benefits of RA supplementation in moderating L-DOPA–induced dyskinesia.
- Published
- 2019
14. Aldehyde dehydrogenase 1–positive nigrostriatal dopaminergic fibers exhibit distinct projection pattern and dopamine release dynamics at mouse dorsal striatum
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Xi Chen, Armando G. Salinas, Junbing Wu, Margaret I. Davis, Jing Pan, Huaibin Cai, Wang Zheng, David M. Lovinger, and Carmelo Sgobio
- Subjects
0301 basic medicine ,Striosome ,Science ,Dopamine ,Mice, Transgenic ,Substantia nigra ,Striatum ,Biology ,Aldehyde Dehydrogenase 1 Family ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Dopamine receptor D1 ,medicine ,Animals ,Cells, Cultured ,Dopamine transporter ,Homeodomain Proteins ,Mice, Knockout ,Multidisciplinary ,Pars compacta ,Dopaminergic Neurons ,Dopaminergic ,Retinal Dehydrogenase ,Aldehyde Dehydrogenase ,Corpus Striatum ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,nervous system ,Biochemistry ,alpha-Synuclein ,biology.protein ,Medicine ,030217 neurology & neurosurgery ,Transcription Factors ,medicine.drug - Abstract
Aldehyde dehydrogenase 1 (ALDH1A1)–positive dopaminergic (DA) neurons at the ventral substantia nigra pars compacta (SNpc) preferentially degenerate in Parkinson’s disease (PD). Their projection pattern and dopamine release properties, however, remains uncharacterized. Here we show that ALDH1A1–positive axons project predominantly to the rostral two–thirds of dorsal striatum. A portion of these axons converge on a small fraction of striosome compartments restricted to the dorsolateral striatum (DLS), where less dopamine release was measured compared to the adjacent matrix enriched with the ALDH1A1–negative axons. Genetic ablation of Aldh1a1 substantially increases the dopamine release in striosomes, but not in matrix. Additionally, the presence of PD-related human α-synuclein A53T mutant or dopamine transporter (DAT) blockers also differentially affects the dopamine output in striosomes and matrix. Together, these results demonstrate distinct dopamine release characteristics of ALDH1A1–positive DA fibers, supporting a regional specific function of ALDH1A1 in regulating dopamine availability/release in striatum.
- Published
- 2017
15. Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120
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Satoshi Kaneko, Lei Xiao, Shaokun Shu, Donghwa Kim, Domenico Coppola, Jianping Guo, Zengqiang Yuan, Junbing Wu, and Jin Q. Cheng
- Subjects
Threonine ,Green Fluorescent Proteins ,Immunoblotting ,Active Transport, Cell Nucleus ,AKT1 ,Apoptosis ,Biology ,Mitogen-activated protein kinase kinase ,Protein Serine-Threonine Kinases ,Transfection ,Biochemistry ,Cell Line ,Phosphatidylinositol 3-Kinases ,Chlorocebus aethiops ,Animals ,Humans ,Kinase activity ,Insulin-Like Growth Factor I ,Phosphorylation ,Protein kinase A ,Protein kinase B ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cell Nucleus ,Hippo signaling pathway ,Akt/PKB signaling pathway ,Mechanisms of Signal Transduction ,Intracellular Signaling Peptides and Proteins ,Cell Biology ,Molecular biology ,Cell biology ,Microscopy, Fluorescence ,COS Cells ,Mutation ,Additions and Corrections ,Proto-Oncogene Proteins c-akt ,HeLa Cells ,Protein Binding ,Signal Transduction - Abstract
The protein kinase mammalian sterile 20-like kinase 1 (MST1) is a mammalian homologue of the Drosophila hippo and plays a critical role in regulation of programmed cell death. MST1 exerts pro-apoptotic function through cleavage, autophosphorylation-Thr(183) and subsequent translocation to the nucleus where it phosphorylates a number of molecules, including LATS1/2, FOXO, JNK, and histone H2B. Here, we show that the cleavage of MST1 is inhibited by the phosphatidylinositol 3-kinase/Akt pathway. Akt interacts with MST1 and phosphorylates a highly conserved residue threonine 120 of MST1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of Thr(183). Phospho-MST1-Thr(120) failed to activate downstream targets FOXO3a and JNK. Further, inverse correlation between pMST1-Thr(120) and pMST1-Thr(183) was observed in human ovarian tumors. These findings indicate that the phosphorylation of MST1-Thr(120) by Akt could be a major mechanism of regulation of the Hippo/MST1 pathway by cell survival signaling.
- Published
- 2016
16. DJ-1 promotes the proteasomal degradation of Fis1: implications of DJ-1 in neuronal protection
- Author
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Zheng Zheng, Zengqiang Yuan, Junbing Wu, Yong Tian, Guiping Du, Rong Wu, Qiang Zhang, Jun Ma, and Renjie Jiao
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Male ,FIS1 ,Proteasome Endopeptidase Complex ,Programmed cell death ,Ubiquitin-Protein Ligases ,Protein Deglycase DJ-1 ,AKT1 ,Apoptosis ,Mice, Transgenic ,Biochemistry ,Mitochondrial Proteins ,Mice ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,Parkinsonian Disorders ,Ubiquitin ,Animals ,Molecular Biology ,Protein kinase B ,Neurons ,Oncogene Proteins ,biology ,MPTP ,Ubiquitination ,PARK7 ,Membrane Proteins ,Peroxiredoxins ,Cell Biology ,Molecular biology ,Mitochondria ,Cell biology ,chemistry ,biology.protein ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Mutations in DJ-1/PARK7 (Parkinson protein 7) have been identified as a cause of autosomal-recessive PD (Parkinson's disease) and the antioxidant property of DJ-1 has been shown to be involved in the regulation of mitochondrial function and neuronal cell survival. In the present study, we first found that the DJ-1 transgene mitigated MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced DA (dopamine) neuron cell death and cell loss. We then observed that the protein levels of DJ-1 were significantly decreased, whereas levels of Fis1 [fission 1 (mitochondrial outer membrane) homologue] were noticeably increased in the striatum of MPTP-treated mice. In addition to our identification of RNF5 (RING-finger protein-5) as an E3-ligase for Fis1 ubiquitination, we demonstrated the involvement of the DJ-1/Akt/RNF5 signalling pathway in the regulation of Fis1 proteasomal degradation. In other experiments, we found that Akt1 enhances the mitochondrial translocation and E3-ligase activity of RNF5, leading to Fis1 degradation. Together, the identification of Fis1 degradation by DJ-1 signalling in the regulation of oxidative stress-induced neuronal cell death supplies a novel mechanism of DJ-1 in neuronal protection with the implication of DJ-1 in a potential therapeutic avenue for PD.
- Published
- 2012
17. The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death
- Author
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Yan Wang, Weizhe Liu, Peng Hu, Lei Xiao, Mou Cao, Guangju Ji, Dongmei Chen, Zengqiang Yuan, Jian Ren, Yuan Fang, Wenzhi Bi, Junbing Wu, Yanhong Zhao, and Zheng Zheng
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General Neuroscience ,Tyrosine phosphorylation ,Biology ,medicine.disease_cause ,Cell biology ,chemistry.chemical_compound ,chemistry ,FOXO3 ,medicine ,Phosphorylation ,ASK1 ,Signal transduction ,Protein kinase A ,Tyrosine kinase ,Oxidative stress - Abstract
Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. The protein kinase MST1 (mammalian Ste20-like kinase 1) plays a major role in oxidative stress-induced cell death in primary mammalian neurons. However, the mechanisms that regulate MST1 in oxidative stress responses remain largely unknown. In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. Inhibition of c-Abl promotes the degradation of MST1 through C terminus of Hsc70-interacting protein (CHIP)-mediated ubiquitination, and thereby attenuates cell death. Oxidative stress induces the c-Abl-dependent tyrosine phosphorylation of MST1 and increases the interaction between MST1 and FOXO3 (Forkhead box O3), thereby activating the MST1-FOXO signaling pathway, leading to cell death in both primary culture neurons and rat hippocampal neurons. The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST1 suggests that the c-Abl-MST1 signaling cascade plays an important role in cellular responses to oxidative stress.
- Published
- 2011
18. Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export
- Author
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Huaibin Cai, Bo Ma, Loukia Parisiadou, Lixin Sun, Jinhui Ding, Guoxiang Liu, Parvathi Rudrabhatla, Chengsong Xie, Hyun Jin Cho, Zhihua Liu, Xi Chen, Junbing Wu, and Jia Yu
- Subjects
Dendritic spine ,Dendritic Spines ,Recombinant Fusion Proteins ,Mutation, Missense ,Vesicular Transport Proteins ,Golgi Apparatus ,GTPase ,Leucine-rich repeat ,Biology ,Protein Serine-Threonine Kinases ,Endoplasmic Reticulum ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,symbols.namesake ,Mice ,Genes, Reporter ,Protein Interaction Mapping ,Animals ,Humans ,Kinase activity ,Molecular Biology ,Cells, Cultured ,General Immunology and Microbiology ,General Neuroscience ,Endoplasmic reticulum ,Parkinson Disease ,Golgi apparatus ,LRRK2 ,Cell biology ,Transport protein ,nervous system diseases ,Protein Transport ,Have You Seen? ,Gene Expression Regulation ,symbols ,COP-Coated Vesicles ,hormones, hormone substitutes, and hormone antagonists - Abstract
Leucine‐rich repeat kinase 2 (LRRK2) has been associated with Parkinson9s disease (PD) and other disorders. However, its normal physiological functions and pathogenic properties remain elusive. Here we show that LRRK2 regulates the anterograde ER–Golgi transport through anchoring Sec16A at the endoplasmic reticulum exit sites (ERES). LRRK2 interacted and co‐localized with Sec16A, a key protein in the formation of ERES. Lrrk2 depletion caused a dispersion of Sec16A from ERES and impaired ER export. In neurons, LRRK2 and Sec16A showed extensive co‐localization at the dendritic ERES (dERES) that locally regulate the transport of proteins to the dendritic spines. A loss of Lrrk2 affected the association of Sec16A with dERES and impaired the activity‐dependent targeting of glutamate receptors onto the cell/synapse surface. Furthermore, the PD‐related LRRK2 R1441C missense mutation in the GTPase domain interfered with the interaction of LRRK2 with Sec16A and also affected ER–Golgi transport, while LRRK2 kinase activity was not required for these functions. Therefore, our findings reveal a new physiological function of LRRK2 in ER–Golgi transport, suggesting ERES dysfunction may contribute to the pathogenesis of PD.
- Published
- 2014
19. Generation of Calhm1 knockout mouse and characterization of calhm1 gene expression
- Author
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Yumin Hao, Junbing Wu, Shengyi Peng, Guangju Ji, Rong Wu, and Zengqiang Yuan
- Subjects
Male ,Biology ,Biochemistry ,Methylation ,Pathogenesis ,Mice ,Drug Discovery ,medicine ,Animals ,Humans ,RNA, Messenger ,Gene ,Genetics ,Mice, Knockout ,Gene Expression Profiling ,Wild type ,Cell Biology ,Human brain ,Cell biology ,Gene expression profiling ,medicine.anatomical_structure ,CpG site ,Knockout mouse ,CALHM1 ,CpG Islands ,Female ,Calcium Channels ,Biotechnology ,Research Article - Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease among elderly people worldwide. Several genes have been validated to be associated with AD, and calcium homeostasis modulator 1 (Calhm1) is the latest suspected one. To investigate the biological and pathological function of Calhm1 systematically, we generated a Calhm1 conventional knockout mouse. However, both the male and female of elderly Calhm1 knockout (KO) mice showed similar ability to their wild type littermates in spatial learning and memory retrieving. Surprisingly, we found that Calhm1 mRNA could not be detected in mouse brains at different ages, although it is expressed in the human brain tissues. We further found that CpG islands (CGIs) of both mouse and human Calhm1 were hypermethylated, whereas CGI of mouse Calhm2 was hypomethylated. In addition, transcriptional active marker H3K4Di occupied on promoters of human Calhm1 and mouse Calhm2 at a considerable level in brain tissues, while the occupancy of H3K4Di on promoter of mouse Calhm1 was rare. In sum, we found that mouse Calhm1 was of rare abundance in brain tissues. So it might not be suitable to utilize the knockout murine model to explore biological function of Calhm1 in the pathogenesis of AD.
- Published
- 2012
20. Regulation of neuronal cell death by c-Abl-Hippo/MST2 signaling pathway
- Author
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Weizhe Liu, Zengqiang Yuan, Zheng Zheng, Junbing Wu, Aiqin Qu, Lei Xiao, and Yujie Bai
- Subjects
lcsh:Medicine ,Mitogen-activated protein kinase kinase ,Protein Serine-Threonine Kinases ,Serine-Threonine Kinase 3 ,Developmental Neuroscience ,Molecular Cell Biology ,Tyrosine Kinase Signaling Cascade ,Humans ,Signaling in Cellular Processes ,ASK1 ,Phosphorylation ,lcsh:Science ,Protein kinase A ,Proto-Oncogene Proteins c-abl ,Biology ,Apoptotic Signaling Cascade ,MAPK14 ,Apoptotic Signaling ,Cellular Stress Responses ,Neurons ,Hippo signaling pathway ,Multidisciplinary ,biology ,MAP kinase kinase kinase ,Cell Death ,Protein Kinase Signaling Cascade ,lcsh:R ,Cyclin-dependent kinase 2 ,Signaling Cascades ,Cell biology ,Oxidative Stress ,HEK293 Cells ,biology.protein ,lcsh:Q ,Cyclin-dependent kinase 9 ,Organism Development ,HeLa Cells ,Signal Transduction ,Research Article ,Developmental Biology ,Neuroscience - Abstract
BACKGROUND: Mammalian Ste20-like kinases (MSTs) are the mammalian homologue of Drosophila hippo and play critical roles in regulation of cell death, organ size control, proliferation and tumorigenesis. MSTs exert pro-apoptotic function through cleavage, autophosphorylation and in turn phosphorylation of downstream targets, such as Histone H2B and FOXO (Forkhead box O). Previously we reported that protein kinase c-Abl mediates oxidative stress-induced neuronal cell death through phosphorylating MST1 at Y433, which is not conserved among mammalian MST2, Drosophila Hippo and C.elegans cst-1/2. METHODOLOGY/PRINCIPAL FINDINGS: Using immunoblotting, in vitro kinase and cell death assay, we demonstrate that c-Abl kinase phosphorylates MST2 at an evolutionarily conserved site, Y81, within the kinase domain. We further show that the phosphorylation of MST2 by c-Abl leads to the disruption of the interaction with Raf-1 proteins and the enhancement of homodimerization of MST2 proteins. It thereby enhances the MST2 activation and induces neuronal cell death. CONCLUSIONS/SIGNIFICANCE: The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST2 suggests that the conserved c-Abl-MST signaling cascade plays an important role in oxidative stress-induced neuronal cell death.
- Published
- 2011
21. Methylation-mediated regulation of E2F1 in DNA damage-induced cell death
- Author
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Yadong Wang, Yu Sun, Pinchao Mei, Yujie Bai, Junbing Wu, Zengqiang Yuan, Qi Xie, and Ye Zhang
- Subjects
endocrine system ,Programmed cell death ,Transcription, Genetic ,DNA damage ,Molecular Sequence Data ,Biology ,Biochemistry ,Methylation ,Cell Line ,chemistry.chemical_compound ,E2F1 ,Humans ,Epigenetics ,Amino Acid Sequence ,Molecular Biology ,Epigenomics ,Histone Demethylases ,Cell Death ,Protein Stability ,Lysine ,Cell Biology ,Histone-Lysine N-Methyltransferase ,chemistry ,Apoptosis ,Gene Knockdown Techniques ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Tumor Suppressor Protein p53 ,DNA ,E2F1 Transcription Factor ,DNA Damage - Abstract
E2F1 promotes DNA damage-induced apoptosis and the post-translational modifications of E2F1 play an important role in the regulation of E2F1-mediated cell death. Here, we found that Set9 and LSD1 regulate E2F1-mediated apoptosis upon DNA damage. Set9 methylates E2F1 at lysine 185, a conserved residue in the DNA-binding domain of E2F family proteins. The methylation of E2F1 by Set9 leads to the stabilization of E2F1 and up-regulation of its proapoptotic target genes p73 and Bim, and thereby induces E2F1-mediated apoptosis in response to genotoxic agents. We also found that LSD1 demethylates E2F1 at lysine 185 and reduces E2F1-mediated cell death. The identification of the methylation/demethylation of E2F1 by Set9/LSD1 suggests that E2F1 is dynamically regulated by epigenetic enzymes in response to DNA damage.
- Published
- 2011
22. MST1 Promotes Apoptosis through Regulating Sirt1-dependent p53 Deacetylation*
- Author
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Guangju Ji, Beibei Mao, Zengqiang Yuan, Yan Wang, Junbing Wu, Qi Xie, Fang Yuan, Yongli Dong, Wenzhi Bi, Yujie Bai, and Wufan Tao
- Subjects
Transcriptional Activation ,p38 mitogen-activated protein kinases ,Apoptosis ,Serine threonine protein kinase ,Protein Serine-Threonine Kinases ,Biochemistry ,MAP2K7 ,Mice ,Sirtuin 1 ,Proto-Oncogene Proteins ,Animals ,Humans ,ASK1 ,Phosphorylation ,Protein kinase A ,Molecular Biology ,biology ,Kinase ,Hepatocyte Growth Factor ,Intracellular Signaling Peptides and Proteins ,Acetylation ,Cell Biology ,Fibroblasts ,HCT116 Cells ,Mice, Mutant Strains ,HEK293 Cells ,Cancer research ,biology.protein ,Signal transduction ,Tumor Suppressor Protein p53 ,Signal Transduction ,DNA Damage - Abstract
Mammalian Sterile 20-like kinase 1 (MST1) protein kinase plays an important role in the apoptosis induced by a variety of stresses. The MST1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, JNK/p38, histone H2B and FOXO. It has been reported that overexpression of MST1 initiates apoptosis by activating p53. However, the molecular mechanisms underlying MST1-p53 signaling during apoptosis are unclear. Here, we report that MST1 promotes genotoxic agent-induced apoptosis in a p53-dependent manner. We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity. Collectively, these findings define a novel regulatory mechanism involving the phosphorylation of Sirt1 by MST1 kinase which leads to p53 activation, with implications for our understanding of signaling mechanisms during DNA damage-induced apoptosis.
- Published
- 2011
23. c-Jun N-terminal kinase enhances MST1-mediated pro-apoptotic signaling through phosphorylation at serine 82
- Author
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Lei Xiao, Guangju Ji, Qi Xie, Jian Ren, Wenzhi Bi, Zengqiang Yuan, Junbing Wu, and Yunfeng Jia
- Subjects
Apoptosis ,Mitogen-activated protein kinase kinase ,Biology ,Biochemistry ,MAP2K7 ,Cell Line ,Proto-Oncogene Proteins ,Serine ,Animals ,Humans ,ASK1 ,c-Raf ,Phosphorylation ,Molecular Biology ,MAPK14 ,Serine/threonine-specific protein kinase ,Feedback, Physiological ,MAP kinase kinase kinase ,Hepatocyte Growth Factor ,Forkhead Box Protein O3 ,JNK Mitogen-Activated Protein Kinases ,Forkhead Transcription Factors ,Cell Biology ,Cell biology ,Enzyme Activation ,Cancer research ,cGMP-dependent protein kinase ,Signal Transduction - Abstract
Protein kinases play an important role in the maintenance of homeostasis between cell survival and apoptosis. Deregulation of these kinases leads to various pathological manifestations, such as cancer and neurodegenerative diseases. The MST1 encodes a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn phosphorylates its downstream targets, Histone H2B and FOXO. However, the upstream regulators of MST1 kinase have been poorly studied. In this study, we report that JNK (c-Jun N-terminal kinase) phosphorylates MST1 at serine 82, which leads to the enhancement of MST1 activation. Accordingly, the activation of MST1 phosphorylates FOXO3 at serine 207 and promotes cell death. The inhibition of JNK kinase per se attenuates MST1 activity and nuclear translocation as well as MST1-induced apoptosis. We also find the S82A (serine mutated to alanine) diminishes MST1 activation and its effect on the FOXO transcription activity. Collectively, these findings define the novel feedback regulation of MST1 kinase activation by its putative substrate, JNK, with implication for our understanding of the signaling mechanism during cell death.
- Published
- 2009
24. DJ-1 promotes the proteasomal degradation of Fis1: implications of DJ-1 in neuronal protection.
- Author
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Qiang ZHANG, Junbing WU, Rong WU, Jun MA, Guiping DU, Renjie JIAO, Yong TIAN, Zheng ZHENG, and Zengqiang YUAN
- Subjects
- *
PROTEASOMES , *GENETIC mutation , *PARKINSON'S disease , *ANTIOXIDANTS , *LABORATORY mice , *MITOCHONDRIAL membranes - Abstract
Mutations in DJ-1/PARK7 (Parkinson protein 7) have been identified as a cause of autosomal-recessive PD (Parkinson's disease) and the antioxidant property of DJ-1 has been shown to be involved in the regulation of mitochondrial function and neuronal cell survival. In the present study, we first found that the DJ-1 transgene mitigated MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine)-induced DA (dopamine) neuron cell death and cell loss. We then observed that the protein levels of DJ-1 were significantly decreased, whereas levels of Fis1 [fission 1 (mitochondrial outer membrane) homologue] were noticeably increased in the striatum of MPTP-treated mice. In addition to our identification of RNF5 (RING-finger protein-5) as an E3-ligase for Fis1 ubiquitination, we demonstrated the involvement of the DJ-1/Akt/RNF5 signalling pathway in the regulation of Fis1 proteasomal degradation. In other experiments, we found that Akt1 enhances the mitochondrial translocation and E3- ligase activity of RNF5, leading to Fis1 degradation. Together, the identification of Fis1 degradation by DJ-1 signalling in the regulation of oxidative stress-induced neuronal cell death supplies a novel mechanism of DJ-1 in neuronal protection with the implication of DJ-1 in a potential therapeutic avenue for PD. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
25. The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death.
- Author
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Lei Xiao, Dongmei Chen, Peng Hu, Junbing Wu, Weizhe Liu, Yanhong Zhao, Mou Cao, Yuan Fang, Wenzhi Bi, Zheng Zheng, Jian Ren, Guangju Ji, Yan Wang, and Zengqiang Yuan
- Subjects
OXIDATIVE stress ,CELL death ,PROTEIN-tyrosine kinases ,OXIDATION-reduction reaction ,PROTEIN kinases ,TYROSINE - Abstract
Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. The protein kinase MST1 (mammalian Ste20-like kinase 1) plays a major role in oxidative stress-induced cell death in primary mammalian neurons. However, the mechanisms that regulate MST1 in oxidative stress responses remain largely unknown. In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. Inhibition of c-Abl promotes the degradation of MST1 through C terminus of Hsc70-interacting protein (CHIP)- mediated ubiquitination, and thereby attenuates cell death. Oxidative stress induces the c-Abl-dependent tyrosine phosphorylation of MST1 and increases the interaction between MST1 and FOXO3 (Forkhead box O3), thereby activating the MST1-FOXO signaling pathway, leading to cell death in both primary culture neurons and rat hippocampal neurons. The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST1 suggests that the c-Abl-MST1 signaling cascade plays an important role in cellular responses to oxidative stress. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
26. MST1 Promotes Apoptosis through Regulating Sirt1 -dependent p53 Deacetylation.
- Author
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Fang Yuan, Qi Xie, Junbing Wu, Yujie Bai, Beibei Mao, Yongli Dong, Wenzhi Bi, Guangju Ji, Wufan Tao, Yan Wang, and Zengqiang Yuan
- Subjects
- *
PROTEIN kinases , *APOPTOSIS , *SIRTUINS , *P53 protein , *ACETYLATION - Abstract
Mammalian Sterile 20-like kinase 1 (MST1) protein kinase plays an important role in the apoptosis induced by a variety of stresses. The MST1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, JNK/p38, histone H2B and FOXO. It has been reported that overexpression of MST1 initiates apoptosis by activating p53. However, the molecular mechanisms underlying MST1-p53 signaling during apoptosis are unclear. Here, we report that MST1 promotes genotoxic agent-induced apoptosis in a p53-dependent manner. We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity. Collectively, these findings define a novel regulatory mechanism involving the phosphorylation of Sirt1 by MST1 kinase which leads to p53 activation, with implications for our understanding of signaling mechanisms during DNA damage-induced apoptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
27. c-Jun N-terminal Kinase Enhances MST1 -mediated Pro-apoptotic Signaling through Phosphorylation at Serine 82.
- Author
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Wenzhi Bi, Lei Xiao, Yunfeng Jia, Junbing Wu, Qi Xie, Jian Ren, Guangju Ji, and Zengqiang Yuan
- Subjects
- *
PROTEIN kinases , *HOMEOSTASIS , *PHOSPHORYLATION , *APOPTOSIS , *CELLULAR control mechanisms , *CELL death , *SERINE - Abstract
Protein kinases play an important role in the maintenance of homeostasis between cell survival and apoptosis. Deregulation of these kinases leads to various pathological manifestations, such as cancer and neurodegenerative diseases. The MST1 encodes a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn phosphorylates its downstream targets, Histone H2B and FOXO. However, the upstream regulators of MST1 kinase have been poorly studied. In this study, we report that JNK (c-Jun N-terminal kinase) phosphorylates MST1 at serine 82, which leads to the enhancement of MST1 activation. Accordingly, the activation of MST1 phosphorylates FOXO3 at serine 207 and promotes cell death. The inhibition of JNK kinaseperse attenuates MST1 activity and nuclear translocation as well as MST1-induced apoptosis. We also find the S82A (serine mutated to alanine) diminishes MST1 activation and its effect on the FOXO transcription activity. Collectively, these findings define the novel feedback regulation of MST-1 kinase -activation by its putative substrate, JNK, with implication for our understanding of the signaling mechanism during cell death. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
28. Phosphoinositide 3-Kinase/Akt Inhibits MST1-Mediated Pro-apoptotic Signaling through Phosphorylation of Threonine 120.
- Author
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Zengqiang Yuan, Donghwa Kim, Shaokun Shu, Junbing Wu, Jianping Guo, Lei Xiao, Kaneko, Satoshi, CoppoIa, Domenico, and Cheng, Jin Q.
- Subjects
- *
PROTEIN kinases , *PHOSPHOINOSITIDES , *PHOSPHORYLATION , *DROSOPHILA genetics , *CHROMOSOMAL translocation , *CELL death , *HISTONES - Abstract
The protein kinase mammalian sterile 20-like kinase 1 (MST1) is a mammalian homologue of the Drosophila hippo and plays a critical role in regulation of programmed cell death. MST1 exerts pro-apoptotic function through cleavage, auto-phosphorylation-Thr183 and subsequent translocation to the nucleus where it phosphorylates a number of molecules, including LATS1/2, FOXO, JNK, and histone H2B. Here, we show that the cleavage of MST1 is inhibited by the phosphatidylinositol 3-kinase/Akt pathway. Akt interacts with MST1 and phosphorylates a highly conserved residue threonine 120 of MST1, which leads to inhibition of its kinase activity and nuclear transloca- tion as well as the autophosphorylation of Thr183. Phospho-MST1-Thr12° failed to activate downstream targets FOXO3a and JNK. Further, inverse correlation between pMST1-Thr120 and pMST1-Thr183 was observed in human ovarian tumors. These findings indicate that the phosphorylation of MST1-Thr120 by Akt could be a major mechanism of regulation of the Hippo/MST1 pathway by cell survival signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
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