Loss of spectrin or ankyrin in the presynaptic motoneuron disrupts the synaptic microtubule cytoskeleton and leads to disassembly of the neuromuscular junction (NMJ). Here, we demonstrate that NMJ disassembly after loss of alpha-spectrin can be suppressed by expression of a Wld(S) transgene, providing evidence for a Wallerian-type degenerative mechanism. We then identify a second signaling system. Enhanced MAPK-JNK-Fos signaling suppresses NMJ disassembly despite loss of presynaptic alpha-spectrin or ankyrin2-L. This signaling system is activated after an acute cytoskeletal disruption, suggesting an endogenous role during neurological stress. This signaling system also includes delayed, negative feedback via the JNK phosphatase puckered, which inhibits JNK-Fos to allow NMJ disassembly in the presence of persistent cytoskeletal stress. Finally, the MAPK-JNK pathway is not required for baseline NMJ stabilization during normal NMJ growth. We present a model in which signaling via JNK-Fos functions as a stress response system that is transiently activated after cytoskeletal disruption to enhance NMJ stability, and is then shut off allowing NMJ disassembly during persistent cytoskeletal disruption.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762090 | PMC |
| http://dx.doi.org/10.1083/jcb.200903166 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice.
Mol Ther
July 2024
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address:
The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed.
View Article and Find Full Text PDFThe cell polarity protein Vangl2 in the muscle shapes the neuromuscular synapse by binding to and regulating the tyrosine kinase MuSK.
Sci Signal
May 2022
Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Institut de Myologie, Centre de Recherche en Myologie, Paris 75013, France.
The development of the neuromuscular junction (NMJ) requires dynamic trans-synaptic coordination orchestrated by secreted factors, including Wnt family morphogens. To investigate how these synaptic cues in NMJ development are transduced, particularly in the regulation of acetylcholine receptor (AChR) accumulation in the postsynaptic membrane, we explored the function of Van Gogh-like protein 2 (Vangl2), a core component of Wnt planar cell polarity signaling. We found that conditional, muscle-specific ablation of in mice reproduced the NMJ differentiation defects seen in mice with global deletion.
View Article and Find Full Text PDFNeuromuscular Junction Dysfunction in Amyotrophic Lateral Sclerosis.
Mol Neurobiol
March 2022
Department of Research, Sir Ganga Ram Hospital, Delhi, India.
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons leading to skeletal muscle denervation. Earlier studies have shown that motor neuron degeneration begins in motor cortex and descends to the neuromuscular junction (NMJ) in a dying forward fashion. However, accumulating evidences support that ALS is a distal axonopathy where early pathological changes occur at the NMJ, prior to onset of clinical symptoms and propagates towards the motor neuron cell body supporting "dying back" hypothesis.
View Article and Find Full Text PDFDissection of Single Skeletal Muscle Fibers for Immunofluorescent and Morphometric Analyses of Whole-Mount Neuromuscular Junctions.
J Vis Exp
August 2021
Developmental Biology Laboratory, Histology and Embryology Department, Faculty of Medicine, Universidad de la República; Cell and Molecular Neurobiology Laboratory, Clemente Estable Biology Research Institute (IIBCE), Ministerio de Educación y Cultura.
The neuromuscular junction (NMJ) is a specialized point of contact between the motor nerve and the skeletal muscle. This peripheral synapse exhibits high morphological and functional plasticity. In numerous nervous system disorders, NMJ is an early pathological target resulting in neurotransmission failure, weakness, atrophy, and even in muscle fiber death.
View Article and Find Full Text PDFTDP-43 Regulation of AChE Expression Can Mediate ALS-Like Phenotype in Zebrafish.
Cells
January 2021
Team "Translational Research for Neuronlogical Diseases", Institut Imagine Inserm U1163, Université de Paris; Sorbonne Université, Université Pierre et Marie Curie (UPMC), Université de Paris 06, Unité Mixte 75, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1127, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 7225 Institut du Cerveau et de la Moelle Épinière (ICM), 75013 Paris, France.
The "distal axonopathy" hypothesis in amyotrophic lateral sclerosis (ALS) proposes that pathological changes occur at the neuromuscular junction (NMJ) early in the disease. While acetylcholinesterase (AChE) plays an important role in the functionality of the NMJ, its potential role in ALS remains unexplored. Here, we identified AChE as a limiting factor regulating muscle/motor neuron connection in a vertebrate model of ALS.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!