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Synaptogenesis and myopathy under acetylcholinesterase overexpression
E Lev-Lehman1, T Evron, R S Broide
1Department of Biological Chemistry, The Life Sciences Institute, The Hebrew University of Jerusalem, Israel.
Journal of Molecular Neuroscience : MN
|June 15, 2000
Summary
Neuromuscular junction (NMJ) stress, from various insults, elevates acetylcholinesterase (AChE) and c-Fos. This leads to neurite outgrowth, synaptogenesis, and muscle pathology, implicating AChE in myopathies.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Neuromuscular junction (NMJ) dysfunction can lead to debilitating myopathies.
- The molecular mechanisms linking NMJ insults to long-term muscle pathology remain unclear.
Purpose of the Study:
- To investigate the molecular responses to cholinergic NMJ stress.
- To identify molecular elements linking NMJ dysfunction to myopathies.
Main Methods:
- Utilized transgenic mice overexpressing synaptic acetylcholinesterase (AChE-S) and diisopropylfluorophosphonate (DFP) treatment.
- Analyzed gene expression, focusing on c-Fos and AChE variants.
- Employed antisense oligonucleotides to target AChE mRNA.
Main Results:
- Elevated c-Fos and readthrough AChE (AChE-R) mRNA observed in stressed NMJs.
- DFP and AChE-S models showed exaggerated neurite branching, disorganized muscle fibers, and NMJ proliferation.
- Antisense oligonucleotides targeting AChE mRNA reduced AChE upregulation and NMJ proliferation.
Conclusions:
- Common transcriptional responses, including increased AChE and c-Fos, occur under cholinergic NMJ stress.
- Deregulated AChE expression is implicated in excessive neurite outgrowth, synaptogenesis, and myopathology.
- Findings provide molecular insights into NMJ dysfunction-induced myopathies.