5 results on '"Xu-Xu Zhuang"'
Search Results
2. Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow
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Chenglong Xie, Xu-Xu Zhuang, Zhangming Niu, Ruixue Ai, Sofie Lautrup, Shuangjia Zheng, Yinghui Jiang, Ruiyu Han, Tanima Sen Gupta, Shuqin Cao, Maria Jose Lagartos-Donate, Cui-Zan Cai, Li-Ming Xie, Domenica Caponio, Wen-Wen Wang, Tomas Schmauck-Medina, Jianying Zhang, He-ling Wang, Guofeng Lou, Xianglu Xiao, Wenhua Zheng, Konstantinos Palikaras, Guang Yang, Kim A. Caldwell, Guy A. Caldwell, Han-Ming Shen, Hilde Nilsen, Jia-Hong Lu, and Evandro F. Fang
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Amyloid beta-Peptides ,Molecular medicine ,High-throughput screening ,Mitophagy ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Article ,Computer Science Applications ,Machine Learning ,Mice ,Alzheimer Disease ,Autophagy ,Animals ,Caenorhabditis elegans ,Biotechnology - Abstract
A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals’ memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational–experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis., Two potent mitophagy inducers, identified and characterized via unsupervised machine learning and a cross-species screening approach, ameliorated the pathology of Alzheimer’s disease in worms and mice.
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- 2022
3. Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models
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Min Li, Xu-Xu Zhuang, Ju-Xian Song, Zhou Zhu, Yuan Tan, Zhijian Huang, Jieqiong Tan, Jia-Hong Lu, Cui-Zan Cai, Huanxing Su, Zi-Ying Wang, Sheng-Fang Wang, and Ming-Yue Wu
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Cell death ,Cancer Research ,Programmed cell death ,Curcumin ,Parkinson's disease ,Immunology ,ATG5 ,Oxidative phosphorylation ,Ascorbic Acid ,medicine.disease_cause ,Neuroprotection ,Article ,Antiparkinson Agents ,Cellular and Molecular Neuroscience ,Parkinsonian Disorders ,Cell Line, Tumor ,Macroautophagy ,medicine ,Autophagy ,Animals ,Humans ,Naphthyridines ,lcsh:QH573-671 ,Oxidopamine ,Behavior, Animal ,Chemistry ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,lcsh:Cytology ,Dopaminergic Neurons ,TOR Serine-Threonine Kinases ,Mitophagy ,Brain ,Cell Biology ,Ascorbic acid ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,nervous system ,TFEB ,Female ,Oxidative stress ,Signal Transduction - Abstract
Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson’s disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.
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- 2020
4. Lycorine, a natural alkaloid, promotes the degradation of alpha-synuclein via PKA-mediated UPS activation in transgenic Parkinson's disease models
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Jieqiong Tan, Xu-Xu Zhuang, Ning-Ning Yuan, Cui-Zan Cai, Huanxing Su, Jia-Hong Lu, Jia-Yue Chen, Qi Zhu, and Yan Chen
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Genetically modified mouse ,Male ,Proteasome Endopeptidase Complex ,animal diseases ,Transgene ,Pharmaceutical Science ,Mice, Transgenic ,PC12 Cells ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Drug Discovery ,Autophagy ,Cyclic AMP ,Animals ,Humans ,Protein kinase A ,030304 developmental biology ,Pharmacology ,Alpha-synuclein ,0303 health sciences ,Ubiquitin ,Parkinson Disease ,Lycorine ,Cyclic AMP-Dependent Protein Kinases ,Cell biology ,Phenanthridines ,Rats ,Up-Regulation ,Disease Models, Animal ,Neuroprotective Agents ,nervous system ,Complementary and alternative medicine ,chemistry ,Proteasome ,Cell culture ,030220 oncology & carcinogenesis ,Amaryllidaceae Alkaloids ,alpha-Synuclein ,Molecular Medicine - Abstract
Background Parkinson's disease (PD) is one of the most common neurodegenerative motor disorders, and is characterized by the presence of Lewy bodies containing misfolded α-synuclein (α-syn) and by selective degeneration of midbrain dopamine neurons. Studies have shown that upregulation of ubiquitin-proteasome system (UPS) activity promotes the clearance of aggregation-prone proteins such as α-syn and Tau, so as to alleviate the neuropathology of neurodegenerative diseases. Purpose To identify and investigate lycorine as a UPS enhancer able to decrease α-syn in transgenic PD models. Methods Dot blot was used to screen α-syn-lowering compounds in an inducible α-syn overexpression cell model. Inducible wild-type (WT) and mutant α-syn-overexpressing PC12 cells, WT α-syn-overexpressing N2a cells and primary cultured neurons from A53T transgenic mice were used to evaluate the effects of lycorine on α-syn degradation in vitro. Heterozygous A53T transgenic mice were used to evaluate the effects of lycorine on α-syn degradation in vivo. mCherry-GFP-LC3 reporter was used to detect autophagy-dependent degradation. Ub-R-GFP and Ub-G76V-GFP reporters were used to detect UPS-dependent degradation. Proteasome activity was detected by fluorogenic substrate Suc-Leu-Leu-Val-Tyr-AMC (Suc-LLVY-AMC). Results Lycorine significantly promoted clearance of over-expressed WT and mutant α-syn in neuronal cell lines and primary cultured neurons. More importantly, 15 days’ intraperitoneal administration of lycorine effectively promoted the degradation of α-syn in the brains of A53T transgenic mice. Mechanistically, lycorine accelerated α-syn degradation by activating cAMP-dependent protein kinase (PKA) to promote proteasome activity. Conclusion Lycorine is a novel α-syn-lowering compound that works through PKA-mediated UPS activation. This ability to lower α-syn implies that lycorine has the potential to be developed as a pharmaceutical for the treatment of neurodegenerative diseases, such as PD, associated with UPS impairment and protein aggregations.
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- 2020
5. NRBF2 is a RAB7 effector required for autophagosome maturation and mediates the association of APP-CTFs with active form of RAB7 for degradation
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Jia-Hong Lu, Cui-Zan Cai, Ju-Xian Song, Huanxing Su, Xu-Xu Zhuang, Ning-Ning Yuan, Jieqiong Tan, Min Li, Yitao Wang, Christian Behrends, Beisha Tang, King-Ho Cheung, Ming-Yue Wu, Siva Sundara Kumar Durairajan, Chuanbin Yang, and Zhenyu Yue
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0301 basic medicine ,Autophagosome ,Autophagosome maturation ,Autophagy-Related Proteins ,Class iii ,Endosomes ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Alzheimer Disease ,Autophagy ,Animals ,Phosphatidylinositol ,Molecular Biology ,Amyloid beta-Peptides ,030102 biochemistry & molecular biology ,Effector ,Autophagosomes ,rab7 GTP-Binding Proteins ,Cell Biology ,Cell biology ,030104 developmental biology ,chemistry ,Trans-Activators ,Lysosomes ,Research Paper - Abstract
NRBF2 is a component of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Our previous study has revealed its role in regulating ATG14-associated PtdIns3K activity for autophagosome initiation. In this study, we revealed an unknown mechanism by which NRBF2 modulates autophagosome maturation and APP-C-terminal fragment (CTF) degradation. Our data showed that NRBF2 localized at autolysosomes, and loss of NRBF2 impaired autophagosome maturation. Mechanistically, NRBF2 colocalizes with RAB7 and is required for generation of GTP-bound RAB7 by interacting with RAB7 GEF CCZ1-MON1A and maintaining the GEF activity. Specifically, NRBF2 regulates CCZ1-MON1A interaction with PI3KC3/VPS34 and CCZ1-associated PI3KC3 kinase activity, which are required for CCZ1-MON1A GEF activity. Finally, we showed that NRBF2 is involved in APP-CTF degradation and amyloid beta peptide production by maintaining the interaction between APP and the CCZ1-MON1A-RAB7 module to facilitate the maturation of APP-containing vesicles. Overall, our study revealed a pivotal role of NRBF2 as a new RAB7 effector in modulating autophagosome maturation, providing insight into the molecular mechanism of NRBF2-PtdIns3K in regulating RAB7 activity for macroautophagy/autophagy maturation and Alzheimer disease-associated protein degradation.. Abbreviations: 3xTg AD, triple transgenic mouse for Alzheimer disease; Aβ, amyloid beta peptide; Aβ1-40, amyloid beta peptide 1–40; Aβ1-42, amyloid beta peptide 1–42; AD, Alzheimer disease; APP, amyloid beta precursor protein; APP-CTFs, APP C-terminal fragments; ATG, autophagy related; ATG5, autophagy related 5; ATG7, autophagy related 7; ATG14, autophagy related 14; CCD, coiled-coil domain; CCZ1, CCZ1 homolog, vacuolar protein trafficking and biogenesis associated; CHX, cycloheximide; CQ, chloroquine; DAPI, 4ʹ,6-diamidino-2-phenylindole; dCCD, delete CCD; dMIT, delete MIT; FYCO1, FYVE and coiled-coil domain autophagy adaptor 1; FYVE, Fab1, YGL023, Vps27, and EEA1; GAP, GTPase-activating protein; GDP, guanine diphosphate; GEF, guanine nucleotide exchange factor; GTP, guanine triphosphate; GTPase, guanosine triphosphatase; HOPS, homotypic fusion and vacuole protein sorting; ILVs, endosomal intralumenal vesicles; KD, knockdown; KO, knockout; LAMP1, lysosomal associated membrane protein 1; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MLVs, multilamellar vesicles; MON1A, MON1 homolog A, secretory trafficking associated; NRBF2, nuclear receptor binding factor 2; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; RILP, Rab interacting lysosomal protein; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62, sequestosome 1; UVRAG, UV radiation resistance associated; VPS, vacuolar protein sorting; WT, wild type.
- Published
- 2020
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