APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice
| العنوان: | APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice |
|---|---|
| المؤلفون: | Stephan Kröger, Andromachi Karakatsani, Yoshie Sugiura, Yun Liu, Eric B. Johnson, Joachim Herz, Robert E. Hammer, Christian Tennert, Weichun Lin, Hong Y. Choi |
| المصدر: | eLife, Vol 2 (2013) eLife |
| بيانات النشر: | eLife Sciences Publications, Ltd, 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | nervous system development, Mouse, LRP, Muscle Fibers, Skeletal, Ligands, Amyloid beta-Protein Precursor, 0302 clinical medicine, Amyloid precursor protein, Receptors, Cholinergic, Phosphorylation, Biology (General), Mice, Knockout, 0303 health sciences, Agrin, General Neuroscience, Neurodegeneration, neurodegeneration, P3 peptide, General Medicine, Alzheimer's disease, Cell biology, medicine.anatomical_structure, Medicine, Protein Binding, Signal Transduction, Research Article, ApoE, Mice, 129 Strain, animal structures, QH301-705.5, Science, Neuromuscular Junction, Biology, Transfection, General Biochemistry, Genetics and Molecular Biology, Neuromuscular junction, 03 medical and health sciences, Alzheimer Disease, mental disorders, medicine, Animals, Humans, Protein Interaction Domains and Motifs, LDL-Receptor Related Proteins, 030304 developmental biology, Acetylcholine receptor, General Immunology and Microbiology, Receptor Protein-Tyrosine Kinases, medicine.disease, Biochemistry of Alzheimer's disease, Mice, Inbred C57BL, HEK293 Cells, Developmental Biology and Stem Cells, Receptors, LDL, nervous system, Multiprotein Complexes, Immunology, biology.protein, neuromuscular synapse, Amyloid precursor protein secretase, 030217 neurology & neurosurgery, Neuroscience |
| الوصف: | ApoE, ApoE receptors and APP cooperate in the pathogenesis of Alzheimer’s disease. Intriguingly, the ApoE receptor LRP4 and APP are also required for normal formation and function of the neuromuscular junction (NMJ). In this study, we show that APP interacts with LRP4, an obligate co-receptor for muscle-specific tyrosine kinase (MuSK). Agrin, a ligand for LRP4, also binds to APP and co-operatively enhances the interaction of APP with LRP4. In cultured myotubes, APP synergistically increases agrin-induced acetylcholine receptor (AChR) clustering. Deletion of the transmembrane domain of LRP4 (LRP4 ECD) results in growth retardation of the NMJ, and these defects are markedly enhanced in APP−/−;LRP4ECD/ECD mice. Double mutant NMJs are significantly reduced in size and number, resulting in perinatal lethality. Our findings reveal novel roles for APP in regulating neuromuscular synapse formation through hetero-oligomeric interaction with LRP4 and agrin and thereby provide new insights into the molecular mechanisms that govern NMJ formation and maintenance. DOI: http://dx.doi.org/10.7554/eLife.00220.001Test eLife digest One of the hallmarks of Alzheimer’s disease is the formation of plaques in the brain by a protein called β-amyloid. This protein is generated by the cleavage of a precursor protein, and mutations in the gene that encodes amyloid precursor protein greatly increase the risk of developing a familial, early-onset form of Alzheimer’s disease in middle age. Individuals with a particular variant of a lipoprotein called ApoE (ApoE4) are also more likely to develop Alzheimer’s disease at a younger age than the rest of the population. Due to its prevalence—approximately 20% of the world’s population are carriers of at least one allele—ApoE4 is the single-most important risk factor for the late-onset form of Alzheimer’s disease. Amyloid precursor protein and the receptors for ApoE—in particular one called LRP4—are also essential for the development of the specialized synapse that forms between motor neurons and muscles. However, the mechanisms by which they, individually or together, contribute to the formation of these neuromuscular junctions are incompletely understood. Now, Choi et al. have shown that amyloid precursor protein and LRP4 interact at the developing neuromuscular junction. A protein called agrin, which is produced by motor neurons and which must bind to LRP4 to induce neuromuscular junction formation, also binds directly to amyloid precursor protein. This latter interaction leads to the formation of a complex between LRP4 and amyloid precursor protein that robustly promotes the formation of the neuromuscular junction. Mutations that remove the part of LRP4 that anchors it to the cell membrane weaken this complex and thus reduce the development of neuromuscular junctions in mice, especially if the animals also lack amyloid precursor protein. These three proteins thus seem to influence the development and maintenance of neuromuscular junctions by regulating the activity of a fourth protein, called MuSK, which is present on the surface of muscle cells. Activation of MuSK by agrin bound to LRP4 promotes the clustering of acetylcholine receptors in the membrane, which is a crucial step in the formation of the neuromuscular junction. Intriguingly, Choi et al. have now shown that amyloid precursor protein can, by interacting directly with LRP4, also activate MuSK even in the absence of agrin, albeit only to a small extent. The work of Choi et al. suggests that the complex formed between agrin, amyloid precursor protein and LRP4 helps to focus the activation of MuSK, and thus the clustering of acetylcholine receptors, to the site of the developing neuromuscular junction. Since all four proteins are also found in the central nervous system, similar processes might well be at work during the development and maintenance of synapses in the brain. Further studies of these interactions, both at the neuromuscular junction and in the brain, should shed new light on both normal synapse formation and the synaptic dysfunction that is seen in Alzheimer’s disease. DOI: http://dx.doi.org/10.7554/eLife.00220.002Test |
| تدمد: | 2050-084X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2b9406d8051d9012de9f851dfe99a9e7Test https://doi.org/10.7554/elife.00220Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....2b9406d8051d9012de9f851dfe99a9e7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2050084X |
|---|