Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice.

Autor: Mukhamedyarov MA; Department of Normal Physiology, Kazan State Medial University, 49 Butlerova St., Kazan 420012, Russia., Khabibrakhmanov AN; Department of Normal Physiology, Kazan State Medial University, 49 Butlerova St., Kazan 420012, Russia., Khuzakhmetova VF; Kazan Institute of Biochemistry and Biophysics, Federal Research Center ''Kazan Scientific Center of RAS', 2/31 Lobachevsky St., P.O. Box 30, Kazan 420111, Russia., Giniatullin AR; Department of Normal Physiology, Kazan State Medial University, 49 Butlerova St., Kazan 420012, Russia.; Kazan Institute of Biochemistry and Biophysics, Federal Research Center ''Kazan Scientific Center of RAS', 2/31 Lobachevsky St., P.O. Box 30, Kazan 420111, Russia., Zakirjanova GF; Department of Normal Physiology, Kazan State Medial University, 49 Butlerova St., Kazan 420012, Russia.; Kazan Institute of Biochemistry and Biophysics, Federal Research Center ''Kazan Scientific Center of RAS', 2/31 Lobachevsky St., P.O. Box 30, Kazan 420111, Russia., Zhilyakov NV; Kazan Institute of Biochemistry and Biophysics, Federal Research Center ''Kazan Scientific Center of RAS', 2/31 Lobachevsky St., P.O. Box 30, Kazan 420111, Russia., Mukhutdinova KA; Department of Normal Physiology, Kazan State Medial University, 49 Butlerova St., Kazan 420012, Russia., Samigullin DV; Kazan Institute of Biochemistry and Biophysics, Federal Research Center ''Kazan Scientific Center of RAS', 2/31 Lobachevsky St., P.O. Box 30, Kazan 420111, Russia.; Department of Radiophotonics and Microwave Technologies, Kazan National Research Technical University, 10 K. Marx St., Kazan 420111, Russia., Grigoryev PN; Department of Normal Physiology, Kazan State Medial University, 49 Butlerova St., Kazan 420012, Russia., Zakharov AV; Department of Normal Physiology, Kazan State Medial University, 49 Butlerova St., Kazan 420012, Russia.; Laboratory of Neurobiology, Kazan Federal University, Kazan 420008, Russia., Zefirov AL; Department of Normal Physiology, Kazan State Medial University, 49 Butlerova St., Kazan 420012, Russia., Petrov AM; Department of Normal Physiology, Kazan State Medial University, 49 Butlerova St., Kazan 420012, Russia.; Kazan Institute of Biochemistry and Biophysics, Federal Research Center ''Kazan Scientific Center of RAS', 2/31 Lobachevsky St., P.O. Box 30, Kazan 420111, Russia.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 May 19; Vol. 24 (10). Date of Electronic Publication: 2023 May 19.
DOI: 10.3390/ijms24109022
Abstrakt: Amyotrophic lateral sclerosis (ALS) is manifested as skeletal muscle denervation, loss of motor neurons and finally severe respiratory failure. Mutations of RNA-binding protein FUS are one of the common genetic reasons of ALS accompanied by a 'dying back' type of degeneration. Using fluorescent approaches and microelectrode recordings, the early structural and functional alterations in diaphragm neuromuscular junctions (NMJs) were studied in mutant FUS mice at the pre-onset stage. Lipid peroxidation and decreased staining with a lipid raft marker were found in the mutant mice. Despite the preservation of the end-plate structure, immunolabeling revealed an increase in levels of presynaptic proteins, SNAP-25 and synapsin 1. The latter can restrain Ca 2+ -dependent synaptic vesicle mobilization. Indeed, neurotransmitter release upon intense nerve stimulation and its recovery after tetanus and compensatory synaptic vesicle endocytosis were markedly depressed in FUS mice. There was a trend to attenuation of axonal [Ca 2+ ] in increase upon nerve stimulation at 20 Hz. However, no changes in neurotransmitter release and the intraterminal Ca 2+ transient in response to low frequency stimulation or in quantal content and the synchrony of neurotransmitter release at low levels of external Ca 2+ were detected. At a later stage, shrinking and fragmentation of end plates together with a decrease in presynaptic protein expression and disturbance of the neurotransmitter release timing occurred. Overall, suppression of synaptic vesicle exo-endocytosis upon intense activity probably due to alterations in membrane properties, synapsin 1 levels and Ca 2+ kinetics could be an early sign of nascent NMJ pathology, which leads to neuromuscular contact disorganization.
Databáze: MEDLINE
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