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In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington's disease. In the brain of Alzheimer's disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer's disease and Parkinson's disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.
Subject(s)
Animals , Humans , DNA Methylation , Epigenesis, Genetic , Neurodegenerative Diseases/genetics , Parkinson Disease/genetics , Protein Processing, Post-TranslationalABSTRACT
N-methyladenosine (mA), catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14, is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However, the roles and precise mechanisms of mA modification in regulating neuronal development and adult neurogenesis remain unclear. Here, we examined the function of Mettl3, the key component of the complex, in neuronal development and adult neurogenesis of mice. We found that the depletion of Mettl3 significantly reduced mA levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs. Mettl3 depletion not only inhibited neuronal development and skewed the differentiation of aNSCs more toward glial lineage, but also affected the morphological maturation of newborn neurons in the adult brain. mA immunoprecipitation combined with deep sequencing (MeRIP-seq) revealed that mA was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically, mA was present on the transcripts of histone methyltransferase Ezh2, and its reduction upon Mettl3 knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by Mettl3 depletion could be rescued by Ezh2 overexpression. Collectively, our results uncover a crosstalk between RNA and histone modifications and indicate that Mettl3-mediated mA modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.
Subject(s)
Animals , Adenosine , Metabolism , Adult Stem Cells , Cell Biology , Metabolism , Brain , Metabolism , Cell Differentiation , Genetics , Cell Proliferation , Enhancer of Zeste Homolog 2 Protein , Metabolism , Gene Expression Regulation , Methyltransferases , Metabolism , Mice, Inbred C57BL , Neural Stem Cells , Cell Biology , Metabolism , Neurogenesis , Genetics , Neurons , Cell Biology , Metabolism , RNA, Messenger , Genetics , MetabolismABSTRACT
@#ObjectiveTo observe the effects of neural stem cells transplantation on the behavioral deficits of Parkinson's disease mice.MethodsSpontaneous movement,Morris Water Maze and Rotarod were adopted to evaluate the behavioral changes.ResultsCompared with the control,the time of spontaneous movement was decreased,the latency of Water Maze was lengthened,and the time of Rotarod was shortened in the Parkinson's disease(PD) mice. These deficits were improved 2,4 and 8 weeks after unilateral and bilateral transplantation of neural stem cells.ConclusionsThe transplantation of neural stem cells can improve the behavioral deficits in the PD mice.
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@#ObjectiveTo establish a method of isolation and culture of neural stem cells(NSCs). MethodsTissues of ventral midbrain were isolated from a rat embryo,and the NSCs were cultured stimulated with basic fibroblast growth factor(bFGF)in vitro.The cells were identified by immunocytochemistry.ResultsNSCs proliferated into neurosphere in symmetric and non-symmetric cleavage ways,and differentiated into neuron, astroglia and oligodendrosyte. ConclusionsThe method has been established to isolate and culture the neural stem cells.
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@#ObjectiveTo observe the changes of neurogenesis in the hippocampus of Alzheimer's model mice and the effect of traditional Chinese medicine Nao Fu Cong. MethodsAlzheimer's type dementia of mice was induced by Aβ25-35 icv.Space learning and memorial ability were tested with Morris Water Maze.The activity of NMDA and M receptor were measured with radio-ligand of MK-801 and QNB.Neurogenesis was observed with the BrdU immunohitochemistry.ResultsSpace learning and memorial ability significantly decreased(P<0.05),MK-801 binding increased and QNB binding decreased (P<0.001),BrdU positive cells decreased in hippocampus(P<0.05).After given drugs for 2 weeks,the mentioned changes were improved significantly(P<0.05,P<0.001,P<0.05).ConclusionsThe toxic effect of Aβ25-35 was involved with the inhibitory action of neurogenesis.Promoting the neurogenesis may be one of the mechanism of traditional Chinese medicine to treat the neurodegenerative diseases.
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@#ObjectiveTo determine survival and differentiation of cultured neural stem cells (NSCs) into viable and functional neurons upon transplantation into the brain of MPTP-induced Parkinson's Disease (PD) mode micel.MethodsMice model of PD was established with intraperitoneal (i.p.) injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP,40mg/kg) twice interspersed by 16 hr. Tissues isolated from an embryonic rat midbrain were cultured in clonal density. After labeled with 5-bromo-2′-deoxyuridine (BrdU), the NSCs were transplanted into the uni- or bilateral striatum of PD mice. Tyrosine hydroxylase (TH) immunofluorescence was used to evaluate the toxicity of MPTP on the neural cells in the substantia nigra. Immunohistochemistry and laser confocal were used to detect the survival and differentiation of transplanted NSCs.ResultsTH positive neural cells were significantly reduced in the substantia nigra after MPTP injection. Immunohistology showed that the uni-or bilateral transplanted NSCs could survive in the brains of PD model mice.Some transplanted NSCs could properly differentiate into targeted TH positive neural cells in vivo.ConclusionsThe transplanted multipotent NSCs could survive, differentiate into functional dopamine neurons in the brains of PD model mice.
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@#ObjectiveTo study the effect of XGS Capsule on the femoral head necrosis in mouse and rat. MethodsThe animal model of femoral head necrosis was caused with tretinoin per os. The free locomotive activity, bone density and pathological changed were observed. ResultsIn the model mouse, the free locomotive activity decreased significantly(P<0.01). In the model rat, the density and weight of the bone also decreased(P<0.01). The defects of cartilage, disorders of ossification and dead bone were observed in the femoral head joint. After treatment with XGS Capsule for 5 weeks, these pathological changes significantly improved. Conclusions XGS Capsule was effective in treating the femoral head necrosis.
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AimTo study the effects of aspirin (Asp) and verapamil(Ver)alone or in combination on mesenteric microcirculation of rats. MethodsAcute microcirculation disturbance(AMD) was produced by highmolecular weight dextran(Mr 480, 000) 360 mg· kg-1 iv. Arteriol and venul blood flow velocity and diameter (ABFV, VBFV, AD, VD) and blood flow state(BFS) were observed by intravital microcirculation method. Results Asp 2.5, 5 mg · kg-i, Ver 0.3, 0.6 mg · kg-1,Asp+ Ver(1 + 0.15), (2. 5+ 0. 3) mg· kg-1 iv significant increase ABFV by 11.1%, 31.3%, 18.7%,19.5%, 26.5%, 37.3%, VBFV by 12.5%, 5.7%, 2.5%, 3.7%, 30%, 34.7%,AD by 4.3%, 17.9%, 31.5%, 35%, 20%, 38.1% and VDby 2.2%,4.2%, 25%, 31.5%,5.8%,23.5%espectively, and got a raise in the number of capillaries and a marked improvement of BFS. Asp + Ver(1+0.15, 2.5+0.3) mg · kg-1 iv could reverse AMD. Conclusion Asp is superior to Ver in the increase of BFV, but Ver is superior to Asp in expansion of blood vessel. Asp in combination with Ver produces marked synergistic action and protection againist AMD.