scholarly journals Loss of Tau Expression Attenuates Neurodegeneration Associated with α-Synucleinopathy

2021 ◽  
Author(s):  
Scott C. Vermilyea ◽  
Anne Christensen ◽  
Joyce Meints ◽  
Balvindar Singh ◽  
Héctor Martell-Martínez ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Motor Behavior ◽  
Lewy Bodies ◽  
Motor Deficits ◽  
Post Inoculation ◽  
Neuronal Dysfunction ◽  
Primary Mouse ◽  
Tau Expression

Abstract Background: Neuronal dysfunction and degeneration linked to a-synuclein (aS) pathology is thought to be responsible for the progressive nature of Parkinson’s Disease and related Dementia with Lewy Bodies. Studies indicate to bidirectional pathological relationships between aS pathology and tau abnormalities. We recently showed that A53T mutant human aS (HuaS) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in development of aS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set to determine the role of tau in the onset and progression of aS pathology (a-synucleinopathy) using a transgenic mouse model of a-synucleinopathy lacking mouse tau expression. Methods: Transgenic mice expressing A53T mutant HuaS (TgA53T) were crossed with mTau-/- mice to generate TgA53T/mTau-/-. To achieve uniform induction of a-synucleinopathy in mice, we used intramuscular injections of aS preformed fibrils (PFF) to non-transgenic (nTg), TgA53T, TgA53T/mTau-/-, and mTau-/- mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. Results: Loss of tau expression significantly delayed onset of motor deficits in the TgA53T model and delayed a-synucleinopathy disease progression, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 aS aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, were prevented with tau removal. Conclusions: Collectively, our data suggest that tau is likely acting downstream of aS pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in a-synucleinopathies to identify novel disease-modifying therapeutic strategies.

scholarly journals Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Tang ◽  
Mengchun Zhou ◽  
Rongrong Huang ◽  
Ling Shen ◽  
Li Yang ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Astrocyte Activation ◽  
Hect Domain ◽  
P38 Inhibitor ◽  
Ubiquitin Protein Ligase ◽  
Primary Mouse ◽  
Lps Treatment

Abstract Background Astrocytes participate in innate inflammatory responses within the mammalian central nervous system (CNS). HECT domain E3 ubiquitin protein ligase 1 (HECTD1) functions during microglial activation, suggesting a connection with neuroinflammation. However, the potential role of HECTD1 in astrocytes remains largely unknown. Results Here, we demonstrated that HECTD1 was upregulated in primary mouse astrocytes after 100 ng/ml lipopolysaccharide (LPS) treatment. Genetic knockdown of HECTD1 in vitro or astrocyte-specific knockdown of HECTD1 in vivo suppressed LPS-induced astrocyte activation, whereas overexpression of HECTD1 in vitro facilitated LPS-induced astrocyte activation. Mechanistically, we established that LPS activated σ-1R-JNK/p38 pathway, and σ-1R antagonist BD1047, JNK inhibitor SP600125, or p38 inhibitor SB203580 reversed LPS-induced expression of HECTD1, thus restored LPS-induced astrocyte activation. In addition, FOXJ2 functioned as a transcription factor of HECTD1, and pretreatment of primary mouse astrocytes with BD1047, SB203580, and SP600125 significantly inhibited LPS-mediated translocation of FOXJ2 into the nucleus. Conclusions Overall, our present findings suggest that HECTD1 participates in LPS-induced astrocyte activation by activation of σ-1R-JNK/p38-FOXJ2 pathway and provide a potential therapeutic strategy for neuroinflammation induced by LPS or any other neuroinflammatory disorders.

scholarly journals Deletion of the Actin-Associated Tropomyosin Tpm3 Leads to Reduced Cell Complexity in Cultured Hippocampal Neurons—New Insights into the Role of the C-Terminal Region of Tpm3.1

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 715
Author(s):  
Tamara Tomanić ◽  
Claire Martin ◽  
Holly Stefen ◽  
Esmeralda Parić ◽  
Peter Gunning ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Growth Cones ◽  
Amino Acid Residues ◽  
Terminal Amino Acid ◽  
C Terminus ◽  
Primary Mouse ◽  
Terminal Amino

Tropomyosins (Tpms) have been described as master regulators of actin, with Tpm3 products shown to be involved in early developmental processes, and the Tpm3 isoform Tpm3.1 controlling changes in the size of neuronal growth cones and neurite growth. Here, we used primary mouse hippocampal neurons of C57/Bl6 wild type and Bl6Tpm3flox transgenic mice to carry out morphometric analyses in response to the absence of Tpm3 products, as well as to investigate the effect of C-terminal truncation on the ability of Tpm3.1 to modulate neuronal morphogenesis. We found that the knock-out of Tpm3 leads to decreased neurite length and complexity, and that the deletion of two amino acid residues at the C-terminus of Tpm3.1 leads to more detrimental changes in neurite morphology than the deletion of six amino acid residues. We also found that Tpm3.1 that lacks the 6 C-terminal amino acid residues does not associate with stress fibres, does not segregate to the tips of neurites, and does not impact the amount of the filamentous actin pool at the axonal growth cones, as opposed to Tpm3.1, which lacks the two C-terminal amino acid residues. Our study provides further insight into the role of both Tpm3 products and the C-terminus of Tpm3.1, and it forms the basis for future studies that aim to identify the molecular mechanisms underlying Tpm3.1 targeting to different subcellular compartments.

scholarly journals Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Nicholas P. Marotta ◽  
Jahan Ara ◽  
Norihito Uemura ◽  
Marshall G. Lougee ◽  
Emily S. Meymand ◽  
...  
Keyword(s):  
Cellular Response ◽  
Amyloid Fibrils ◽  
Cultured Cells ◽  
Biological Activities ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Biological Behavior ◽  
Motor Deficits ◽  
Original Material

AbstractLewy bodies (LBs) are complex, intracellular inclusions that are common pathological features of many neurodegenerative diseases. They consist largely of aggregated forms of the protein alpha-Synuclein (α-Syn), which misfolds to give rise to beta-sheet rich amyloid fibrils. The aggregation of monomers into fibrils occurs readily in vitro and pre-formed fibrils (PFFs) generated from recombinant α-Syn monomers are the basis of many models of LB diseases. These α-Syn PFFs recapitulate many pathological phenotypes in both cultured cells and animal models including the formation of α-Syn rich, insoluble aggregates, neuron loss, and motor deficits. However, it is not clear how closely α-Syn PFFs recapitulate the biological behavior of LB aggregates isolated directly from patients. Direct interrogation of the cellular response to LB-derived α-Syn has thus far been limited. Here we demonstrate that α-Syn aggregates derived from LB disease patients induce pathology characterized by a prevalence of large somatic inclusions that is distinct from the primarily neuritic pathology induced by α-Syn PFFs in our cultured neuron model. Moreover, these LB-derived aggregates can be amplified in vitro using recombinant α-Syn to generate aggregates that maintain the unique, somatic pathological phenotype of the original material. Amplified LB aggregates also showed greater uptake in cultured neurons and greater pathological burden and more rapid pathological spread in injected mouse brains, compared to α-Syn PFFs. Our work indicates that LB-derived α-Syn from diseased brains represents a distinct conformation species with unique biological activities that has not been previously observed in fully recombinant α-Syn aggregates and demonstrate a new strategy for improving upon α-Syn PFF models of synucleinopathies using amplified LBs.

Abstract 454: Myeloid CD98hc Deficiency Reduces Atherosclerotic Plaque Development via Impaired Proliferation of Macrophages

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Sara McCurdy ◽  
William A Boisvert
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Atherosclerotic Plaque ◽  
Bone Marrow Cells ◽  
Transmembrane Protein ◽  
Mouse Bone Marrow ◽  
Plaque Development ◽  
Primary Mouse

Macrophage accumulation is a key process affecting all stages of atherosclerosis. Whether these cells accumulate in plaque solely by recruitment of monocytes from circulation or by proliferation within the plaque is an important question that has garnered much interest in recent years. Originally identified as a lymphocyte activation marker, CD98hc (SLC3A2) is a transmembrane protein involved in cell proliferation and survival via integrin signaling and MAP kinase activation. We hypothesized that CD98hc deficiency in myeloid cells would have a protective effect on atherosclerosis development and plaque composition by limiting macrophage proliferation. For the studies described, we utilized mice with myeloid-specific deletion of the CD98hc ( CD98hc fl/fl LysMCre + ) to determine the effects of CD98hc deficiency on macrophage function in the context of atherosclerosis . We performed in vitro assays to investigate the role of CD98hc in the proliferation and survival of primary mouse bone marrow derived macrophages. Although we found no differences in the number of bone marrow cells isolated from control or CD98hc -/- animals, after differentiation with MCS-F for 7 days, the number of macrophages obtained from CD98hc -/- mice was approximately 80% lower (7.2 ± 2.2 x 10 6 vs. 42.4 ± 4.6 x 10 6 per mouse) compared to control mice. Proliferation assays in vitro using EdU revealed approximately 50% (15.4 ± 2.5% vs. 7.5±1.8%) reduced cell proliferation in CD98hc -/- macrophages compared to control cells that could not be rescued with the addition M-CSF. In a 6-week atherosclerosis study using Ldlr -/- CD98hc fl/fl LysMCre + mice, Oil-Red O staining of whole aortae as well as aortic sinus sections showed that atherosclerotic plaque development was reduced compared to Ldlr -/- CD98hc fl/fl LysMCre - control mice. Additionally, immunohistochemical staining of atherosclerotic tissues revealed a reduction in macrophage abundance and proliferation within the plaque of Ldlr -/- CD98hc fl/fl LysMCre + mice compared to control mice. These findings support an important role of CD98hc in macrophage proliferation within the plaque environment, and provide a novel target for reducing atherosclerosis.

scholarly journals Hepatocyte high-mobility group box 1 protects against steatosis and cellular stress during high fat diet feeding

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Minjie Lin ◽  
Jungke Long ◽  
Wenbo Li ◽  
Chenxuan Yang ◽  
Patricia Loughran ◽  
...  
Keyword(s):  
Er Stress ◽  
High Fat Diet ◽  
High Mobility ◽  
High Mobility Group ◽  
High Fat ◽  
Rapid Weight Gain ◽  
Nonalcoholic Fatty Liver ◽  
Primary Mouse

Abstract Background Circulating high-mobility group box 1 (HMGB1) plays important roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Intracellular HMGB1 is critical for the biology of hepatocytes. However, the intracellular role of HMGB1 in hepatocellular steatosis is unknown. Therefore, we aimed to investigate the role of hepatocyte-specific HMGB1 (HC-HMGB1) in development of hepatic steatosis. Methods Wild type (WT) C57BL/6 and HC-HMGB1−/− mice were fed high-fat diet (HFD) or low-fat diet (LFD) for up to 16 weeks. Results As expected, HMGB1 translocated from nuclear into cytoplasm and released into circulation after HFD treatment. HC-HMGB1 deficiency significantly reduced circulating HMGB1, suggesting that hepatocyte is a major source of circulating HMGB1 during NAFLD. Unexpectedly, HC-HMGB1 deficiency promoted rapid weight gain with enhanced hepatic fat deposition compared with WT at as early as 4 weeks after HFD treatment. Furthermore, there was no difference between WT and HC-HMGB1−/− mice in glucose tolerance, energy expenditure, liver damage or systemic inflammation. Interestingly, hepatic gene expression related to free fatty acid (FFA) β-oxidation was significantly down-regulated in HC-HMGB1−/− mice compared with WT, and endoplasmic reticulum (ER) stress markers were significantly higher in livers of HC-HMGB1−/− mice. In vitro experiments using primary mouse hepatocytes showed absence of HMGB1 increased FFA-induced intracellular lipid accumulation, accompanied by increased ER-stress, significant downregulation of FFA β-oxidation, and reduced oxidative phosphorylation. Conclusions Our findings suggest that hepatocyte HMGB1 protects against dysregulated lipid metabolism via maintenance of β-oxidation and prevention of ER stress. This represents a novel mechanism for HMGB1-regulation of hepatocellular steatosis, and suggests that stabilizing HMGB1 in hepatocytes may be effective strategies for prevention and treatment of NAFLD.

Differential Roles of NMDA Receptor Subtypes NR2A and NR2B in Dendritic Branch Development and Requirement of RasGRF1

2010 ◽  
Vol 103 (4) ◽  
pp. 1758-1770 ◽  
Author(s):  
Fernando J. Sepulveda ◽  
Fernando J. Bustos ◽  
Eveling Inostroza ◽  
Felipe A. Zúñiga ◽  
Rachael L. Neve ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Receptor Subtypes ◽  
Dendritic Branch ◽  
Spinal Cord Neurons ◽  
Whole Cell Patch Clamp ◽  
Electrophysiological Recordings ◽  
Branch Formation ◽  
The Individual

N-methyl-d-aspartate receptors (NMDARs) are known to regulate axonal refinement and dendritic branching. However, because NMDARs are abundantly present as tri-heteromers (e.g., NR1/NR2A/NR2B) during development, the precise role of the individual subunits NR2A and NR2B in these processes has not been elucidated. Ventral spinal cord neurons (VSCNs) provide a unique opportunity to address this problem, because the expression of both NR2A and NR2B (but not NR1) is downregulated in culture. Exogenous NR2A or NR2B were introduced into these naturally NR2-null neurons at 4 DIV, and electrophysiological recordings at 11 DIV confirmed that synaptic NR1NR2A receptors and NR1NR2B receptors were formed, respectively. Analysis of the dendritic architecture showed that introduction of NR2B, but not NR2A, dramatically increased the number of secondary and tertiary dendritic branches of VSCNs. Whole cell patch-clamp recordings further indicated that the newly formed branches in NR2B-expressing neurons were able to establish functional synapses because the frequency of miniature AMPA-receptor synaptic currents was increased. Using previously described mutants, we also found that disruption of the interaction between NR2B and RasGRF1 dramatically impaired dendritic branch formation in VSCNs. The differential role of the NR2A and NR2B subunits and the requirement for RasGRF1 in regulating branch formation was corroborated in hippocampal cultures. We conclude that the association between NR1NR2B-receptors and RasGRF1 is needed for dendritic branch formation in VSCNs and hippocampal neurons in vitro. The dominated NR2A expression and the limited interactions of this subunit with the signaling protein RasGRF1 may contribute to the restricted dendritic arbor development in the adult CNS.

scholarly journals Olanzapine inhibits hepatic apolipoprotein A5 secretion inducing hypertriglyceridemia in schizophrenia patients and mice

2021 ◽  
Author(s):  
Xiansheng Huang ◽  
Yiqi Zhang ◽  
Wenqiang Zhu ◽  
Piaopiao Huang ◽  
Jingmei Xiao ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Plasma Triglyceride ◽  
High Dose ◽  
Mrna Levels ◽  
Apolipoprotein A5 ◽  
Protein Levels ◽  
Olanzapine Treatment ◽  
Primary Mouse

Olanzapine, an antipsychotic drug, was reported to induce hypertriglyceridemia, whereas the underlying mechanism remains incompletely understood. This study was to determine the role of apolipoprotein A5 (apoA5) in olanzapine-induced hypertriglyceridemia. In this study, 36 drug-naive and first-episode schizophrenic adult patients (aged 18-60 years) in a multi-center clinical trial (ClinicalTrials.gov NCT03451734) were enrolled. Before and after olanzapine treatment, plasma lipid and apoA5 levels were detected. Moreover, 21 female C57BL/6 J mice (8 weeks old) were divided into 3 groups (n = 7/each group): low-dose olanzapine (3 mg/kg/day), high-dose olanzapine (6 mg/kg/day) and control group. After 6 weeks, plasma glucose, lipids and apoA5 as well as hepatic apoA5 protein and mRNA expression in these animals were detected. In our study in vitro, primary mouse hepatocytes and HepG2 cells were treated with olanzapine of 25, 50, 100 μmol/L, respectively. After 24 hours, apoA5 protein and mRNA levels in hepatocytes were detected. Our study showed that olanzapine treatment significantly increased plasma triglyceride levels and decreased plasma apoA5 levels in these schizophrenic patients. A significant negative correlation was indicated between plasma triglyceride and apoA5 levels in these patients. Consistently, olanzapine dose-dependently increased plasma triglyceride levels and decreased plasma apoA5 levels in mice. Surprisingly, an elevation of hepatic apoA5 protein levels was detected in mice after olanzapine treatment, with no changes of APOA5 mRNA expression. Likewise, olanzapine increased apoA5 protein levels in hepatocytes in vitro, without changes of hepatocyte APOA5 mRNA. Therefore, our study provides the first evidence about the role of apoA5 in olanzapine-induced hypertriglyceridemia. Furthermore, plasma apoA5 reduction, resulting in hypertriglyceridemia, could be attributed to olanzapine-induced inhibition of hepatic apoA5 secretion.

scholarly journals Role of the Thrombin-PAR-1 Pathway in Coxsackievirus Induced Hepatitis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1470-1470
Author(s):  
Kohei Tatsumi ◽  
Silvio Antoniak ◽  
Nigel Mackman
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Primary Mouse Hepatocytes ◽  
Primary Mouse ◽  
Mouse Hepatocytes ◽  
Transplantation Experiments

Abstract Objective: Coxsackievirus B3 (CVB3) can infect different tissues including the heart and liver. Recently, we found that activation of the coagulation cascade and protease-activated receptor 1 (PAR-1) enhances toll-like receptor-3 (TLR3) mediated interferon-β (IFN-β) expression and protects mice from CVB3-induced myocarditis. Here, we investigated the role of PAR-1 in early anti-viral responses in mice and isolated hepatocytes. Methods: Wild-type (WT) and PAR-1 deficient (PAR-1-/-) mice were infected with CVB3 intraperitoneally. The innate immune response, viral load, liver enzyme plasma levels, and inflammation levels were analyzed. Bone-marrow transplantation experiments with the combination of WT mice PAR-1-/- mice were performed to identify the cellular source of PAR-1 contributing to the innate immune response to CVB3. We also analyzed the effect of the direct thrombin inhibition with dabigatran etexilate on CVB3 hepatitis. In addition, we analyzed the effect of PAR-1 activation on TLR3-dependent interferon (IFN)-β expression in primary mouse hepatocytes and the human hepatocyte cell line PH5CH8 in vitro. Results: PAR-1-/- mice exhibited a reduced early innate immune response in the liver at day 4 after infection, which was associated at later times (day 8) to higher viral titers in the liver, increased alanine transaminase plasma levels and more remarkable inflammation compared to control WT mice. Bone marrow transplantation experiments demonstrated that PAR-1 on non-hematopoietic played the major role in the innate immune response of CVB3 hepatitis. Stimulation of PAR-1 with either thrombin or agonist peptide on primary mouse hepatocytes and human PH5CH8 cells in vitro enhanced the antiviral response to dsRNA by increasing IFN-β and C-X-C motif chemokine 10 (CXCL10) expressions, supporting the results of in vivo experiments. Conclusion: Our results suggest that activation of PAR-1 on hepatocytes enhances the innate immune response to CVB3 in the liver. Disclosures No relevant conflicts of interest to declare.

scholarly journals Absence of Thyroid Hormone Induced Delayed Dendritic Arborization in Mouse Primary Hippocampal Neurons Through Insufficient Expression of Brain-Derived Neurotrophic Factor

2021 ◽  
Vol 12 ◽  
Author(s):  
Hiroyuki Yajima ◽  
Izuki Amano ◽  
Sumiyasu Ishii ◽  
Tetsushi Sadakata ◽  
Wataru Miyazaki ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Neurotrophic Factor ◽  
Hippocampal Neurons ◽  
Brain Derived Neurotrophic Factor ◽  
Mrna Levels ◽  
Protein Levels ◽  
Primary Hippocampal Neurons ◽  
Developmental Impairment

Thyroid hormone (TH) plays important roles in the developing brain. TH deficiency in early life leads to severe developmental impairment in the hippocampus. However, the mechanisms of TH action in the developing hippocampus are still largely unknown. In this study, we generated 3,5,3’-tri-iodo-l-thyronine (T3)-free neuronal supplement, based on the composition of neuronal supplement 21 (NS21), to examine the effect of TH in the developing hippocampus using primary cultured neurons. Effects of TH on neurons were compared between cultures in this T3-free culture medium (-T3 group) and a medium in which T3 was added (+T3 group). Morphometric analysis and RT-qPCR were performed on 7, 10, and 14 days in vitro (DIV). On 10 DIV, a decreased dendrite arborization in -T3 group was observed. Such difference was not observed on 7 and 14 DIV. Brain-derived neurotrophic factor (Bdnf) mRNA levels also decreased significantly in -T3 group on 10 DIV. We then confirmed protein levels of phosphorylated neurotrophic tyrosine kinase type 2 (NTRK2, TRKB), which is a receptor for BDNF, on 10 DIV by immunocytochemistry and Western blot analysis. Phosphorylated NTRK2 levels significantly decreased in -T3 group compared to +T3 group on 10 DIV. Considering the role of BDNF on neurodevelopment, we examined its involvement by adding BDNF on 8 and 9 DIV. Addition of 10 ng/ml BDNF recovered the suppressed dendrite arborization induced by T3 deficiency on 10 DIV. We show that the lack of TH induces a developmental delay in primary hippocampal neurons, likely caused through a decreased Bdnf expression. Thus, BDNF may play a role in TH-regulated dendritogenesis.

The Deficiency of Maged1 Attenuates Parkinson's Disease Progression by Inhibiting Apoptosis and Enhancing Autophagy in Mice

2020 ◽  
Author(s):  
Jie Wang ◽  
Wei-Yan You ◽  
Qing Ye ◽  
Jia-Qi Zhang ◽  
Chuan He ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Signaling Pathway ◽  
Knockout Mice ◽  
Gene Transfection ◽  
Motor Deficits ◽  
Mice Model

Abstract Background: Melanoma-associated antigen D1 (Maged1) is expressed in most adult tissues, predominantly in the brain, and has critical functions in the central nervous system in both developmental and adult stages. Loss of Maged1 in mice has been linked to depression, cognitive disorder, circadian rhythm, and drug addiction. However, the role of Maged1 in Parkinson’s disease (PD) remains unclear.Methods: Immunostaining was performed to investigate the expression of Maged1 in the samples from mice and human. To make the acute mice model of PD, C57BL/6 mice and Maged1 knockout mice were injected with 20 mg/kg 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) four times, every 2-hour intervals. SY5Y cells were treated by 200 μM 1-Methyl-4-phenylpyridinium iodide (MPP+). To examine motor balance and coordination, the rotarod test and pole test were used. Then we further investigated the role of Maged1 deficiency in DA neurons by high-performance liquid chromatography, immunohistochemistry, western blot, CCK8 assay, and gene transfection in vivo or in vitro.Results: Maged1 was expressed in DA neurons of samples from mice and human. And the expression of Maged1 was time-dependently upregulated by the treatment with MPTP or MPP+ in vivo or in vitro. Knockout of Maged1 in mice partly rescued the motor deficits and the reduced levels of striatal dopamine and its metabolites by MPTP treatment. Moreover, Maged1 deficiency protected primary DA neurons and differentiated ReNcell VM cells from MPP+ toxicity. Furthermore, along with the overexpression or downregulation of Maged1 in cultured SH-SY5Y cells, the reduced the cell viability by MPP+ treatment was relatively aggerated or attenuated. The effect of Maged1 deficiency may be attributed to the upregulated Akt signaling pathway and the downregulated mTOR signaling pathway, which further attenuated the MPTP or MPP+ -induced cell apoptosis and impairment of autophagy. Consistent with the above data, the degeneration of midbrain and striatum among 15-m Maged1 knockout mice was relatively mild compared to those in 15-m wild-type mice under physiological conditions.Conclusions: Maged1 deficiency-mediated apoptosis inhibition and autophagy enhancement may be a potential pro-survival mechanism during the progression of PD.

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