ABSTRACT
Down syndrome cell adhesion molecule (DSCAM) acts as a netrin-1 receptor and mediates attractive response of axons to netrin-1 in neural development. However, the signaling mechanisms of netrin-DSCAM remain unclear. Here we report that AMP-activated protein kinase (AMPK) interacts with DSCAM through its γ subunit, but does not interact with DCC (deleted in colorectal cancer), another major receptor for netrin-1. Netrin-treatment of cultured cortical neurons leads to increased phosphorylation of AMPK. Both AMPK mutant with dominant-negative effect and AMPK inhibitor can significantly suppress netrin-1 induced neurite outgrowth. Together, these findings demonstrate that AMPK interacts with DSCAM and plays an important role in netrin-1 induced neurite outgrowth. Our study uncovers a previously unknown component, AMPK, in netrin-DSCAM signaling pathway.
Subject(s)
Animals , Humans , Mice , AMP-Activated Protein Kinases , Genetics , Metabolism , Cell Adhesion Molecules , Genetics , Metabolism , Cells, Cultured , HEK293 Cells , Nerve Growth Factors , Pharmacology , Netrin-1 , Neurites , Physiology , Neurons , Cell Biology , Metabolism , Phosphorylation , Protein Binding , Protein Kinase Inhibitors , Pharmacology , RNA Interference , RNA, Small Interfering , Recombinant Fusion Proteins , Genetics , Signal Transduction , Transfection , Tumor Suppressor Proteins , PharmacologyABSTRACT
Mutations in the Fused in sarcoma/Translated in liposarcoma gene (FUS/TLS, FUS) have been identified among patients with amyotrophic lateral sclerosis (ALS). FUS protein aggregation is a major pathological hallmark of FUS proteinopathy, a group of neurodegenerative diseases characterized by FUS-immunoreactive inclusion bodies. We prepared transgenic Drosophila expressing either the wild type (Wt) or ALS-mutant human FUS protein (hFUS) using the UAS-Gal4 system. When expressing Wt, R524S or P525L mutant FUS in photoreceptors, mushroom bodies (MBs) or motor neurons (MNs), transgenic flies show age-dependent progressive neural damages, including axonal loss in MB neurons, morphological changes and functional impairment in MNs. The transgenic flies expressing the hFUS gene recapitulate key features of FUS proteinopathy, representing the first stable animal model for this group of devastating diseases.
Subject(s)
Aged , Animals , Humans , Aging , Genetics , Metabolism , Pathology , Amyotrophic Lateral Sclerosis , Genetics , Metabolism , Pathology , Animals, Genetically Modified , Disease Models, Animal , Drosophila melanogaster , Genetics , Metabolism , Gene Expression , Microscopy, Electron, Scanning , Motor Neurons , Metabolism , Pathology , Mushroom Bodies , Metabolism , Pathology , Mutant Proteins , Genetics , Metabolism , Mutation , Photoreceptor Cells, Invertebrate , Metabolism , Pathology , Plasmids , RNA-Binding Protein FUS , Genetics , Metabolism , Recombinant Fusion Proteins , Genetics , Metabolism , Retinal Degeneration , Pathology , TransfectionABSTRACT
The nervous system is one of the most complicated organ systems in invertebrates and vertebrates. Down syndrome cell adhesion molecule (DSCAM) of the immunoglobulin (Ig) superfamily is expressed widely in the nervous system during embryonic development. Previous studies in Drosophila suggest that Dscam plays important roles in neural development including axon branching, dendritic tiling and cell spacing. However, the function of the mammalian DSCAM gene in the formation of the nervous system remains unclear. Here, we show that Dscam ( del17 ) mutant mice exhibit severe hydrocephalus, decreased motor function and impaired motor learning ability. Our data indicate that the mammalian DSCAM gene is critical for the formation of the central nervous system.
Subject(s)
Animals , Mice , Cell Adhesion Molecules , Genetics , Metabolism , Corpus Callosum , Metabolism , Pathology , Genotype , Hydrocephalus , Genetics , Metabolism , Pathology , Mice, Knockout , Motor Activity , Genetics , Physiology , MutationABSTRACT
Objective To observe the effects of Shenhong (SH) combined with chemotherapeutic drugs on curative effect, symptoms improvement, and immunology function in metaphase or terminal cancer patients.Methods All 598 patients were divided into two groups. The control group had 205 patients treated with chemotherapeutic drugs. The SH-treated group had 393 patients treated with SH combined with chemotherapeutic drugs. Results Compared with control patients, the total remission was 42.0% in SH-treated patients. The improvement rates of pain, cough, debilitation, and anepithymia were 71.9%. The Karnofsky grade was increased by 27.0%. CD+3 and CD+4 were increased by 11.6% and 19.3%, but CD+8was decreased by 22.6% at the same time. The patients CD+4 / CD+8 was enhanced by 54.2%, while the NK cell activity and marophage phagocysis were significantly improved. The content of Ig G and Ig A were increased in the same group. Conclusion The curative effect of SH combined with chemotherapeutic drugs was higher than that of control group. The therapeutic effect of SH is explained by its potential regulation activity on immun system.