Early differences in membrane properties at the neuromuscular junctions of ALS model mice: Effects of 25-hydroxycholesterol
| Autor: | Guzel F. Zakyrjanova, Kamilla A. Mukhutdinova, A. R. Giniatullin, Alexey M. Petrov, Eva A. Kuznetsova |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Ceramide Neuromuscular Junction Ceramides Synaptic Transmission 030226 pharmacology & pharmacy General Biochemistry Genetics and Molecular Biology Neuromuscular junction Lipid peroxidation Mice 03 medical and health sciences chemistry.chemical_compound Membrane Microdomains Superoxide Dismutase-1 0302 clinical medicine medicine Extracellular Animals Choline General Pharmacology Toxicology and Pharmaceutics Muscle Skeletal Neurotransmitter Lipid raft Mice Knockout Amyotrophic Lateral Sclerosis General Medicine Acetylcholine Hydroxycholesterols Cell biology Mice Inbred C57BL Disease Models Animal Cholesterol 030104 developmental biology medicine.anatomical_structure chemistry Female lipids (amino acids peptides and proteins) medicine.drug |
| Zdroj: | Life Sciences. 273:119300 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2021.119300 |
| Popis: | Aims Plasma hyperlipidemia is a protective factor in amyotrophic lateral sclerosis (ALS) while cholesterol-lowering drugs aggravate the pathology. We hypothesize that this phenomenon can be linked with membrane lipid alterations in the neuromuscular junctions (NMJs) occurring before motor neuron loss. Methods Neurotransmitter release in parallel with lipid membrane properties in diaphragm NMJs of SOD1G93A (mSOD) mice at nine weeks of age (pre-onset stage) were assessed. Key findings Despite on slight changes in spontaneous and evoked quantum release of acetylcholine, extracellular levels of choline at resting conditions, an indicator of non-quantum release, were significantly increased in mSOD mice. The use of lipid-sensitive fluorescent probes points to lipid raft disruption in the NMJs of mSOD mice. However, content of cholesterol, a key raft component was unchanged implying another pathway responsible for the loss of raft integrity. In the mSOD mice we found marked increase in levels of raft-destabilizing lipid ceramide. This was accompanied by enhanced ability to uptake of exogenous ceramide in NMJs. Acute and chronic administration of 25-hydroxycholesterol, whose levels increase due to hypercholesterolemia, recovered early alterations in membrane properties. Furthermore, chronic treatment with 25-hydroxycholesterol prevented increase in ceramide and extracellular choline levels as well as suppressed lipid peroxidation of NMJ membranes and fragmentation of end plates. Significance Thus, lipid raft disruption likely due to ceramide accumulation could be early event in ALS which may trigger neuromuscular abnormalities. Cholesterol derivative 25-hydroxycholesterol may serve as a molecule restoring the membrane and functional properties of NMJs at the early stage. |
| Databáze: | OpenAIRE |
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