Review: Neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy

Murray, Lyndsay M.; Talbot, Kevin; Gillingwater, Thomas H.

doi:10.1111/j.1365-2990.2009.01061.x

Cited by 32 publications

(44 citation statements)

References 198 publications

(227 reference statements)

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“…In mice expressing a fALS-inducing SOD1 mutation, one of the earliest signs of disease is degeneration of axons and motor terminals that innervate fast limb muscles (reviewed by Fischer and Glass, 2007; Murray et al, 2010). This degeneration occurs before motor neuron cell bodies degenerate, leading to the suggestion that this disease be classified as a distal axonopathy (Fischer et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Morphological and functional changes in innervation of a fast forelimb muscle in SOD1-G85R mice

Nguyen

Zhang

Barrett

et al. 2012

Neurobiology of Disease

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Muscle endplates become denervated in mice that express mutations of human superoxide dismutase 1 (hSOD1), models of familial amyotrophic lateral sclerosis. This denervation is especially marked in fast limb muscles, and precedes death of motor neuron somata. This study used mice that expressed yellow fluorescent protein (YFP) in neurons to investigate changes in the morphology and function of axons and motor terminals inervating a fast forelimb muscle (epitrochleoanconeus, ETA) in presymptomatic and symptomatic hSOD1-G85R mice, compared to those in mice that express wild-type (wt) hSOD1. The percentage of endplates (identified using fluorescently-labeled α-bungarotoxin) innervated by motor terminals remained high in presymptomatic SOD1-G85R mice, but fell to ~50% in symptomatic mice. The number of large diameter (≥ 4 µm) axons in the ETA nerve also decreased as mice became symptomatic, and endplate innervation correlated best with the number of large diameter axons. Motor terminal function was assessed using changes in terminal YFP fluorescence evoked by trains of action potentials; different components of the pH-dependent YFP signals reflect stimulation-induced Ca2+ entry and vesicular exo/endocytosis. Most visible motor terminals (>90%) remained capable of responding to nerve stimulation in both pre- and symptomatic hSOD1-G85R mice, but with functional alterations. Responses in presymptomatic terminals suggested reduced acidification and increased vesicular release, whereas symptomatic terminals exhibited increased acidification and reduced vesicular release. The fact that most remaining terminals were able to respond to nerve stimulation suggests that motor terminal-protective therapies might contribute to preserving neuromuscular function in fALS mice.

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Section: Introductionmentioning

confidence: 99%

Morphological and functional changes in innervation of a fast forelimb muscle in SOD1-G85R mice

Nguyen

Zhang

Barrett

et al. 2012

Neurobiology of Disease

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“…One conclusion that can be obtained from these data is that a dramatic loss in presynaptic NF labeling does not necessarily indicate that the presynaptic element has degenerated. As discussed later, this conclusion is relevant when we interpret the results of studies in which NF immunoreactivity is used as the sole or main label to mark the presynaptic motor neuron terminal (24).…”

Section: Discussionmentioning

confidence: 93%

Chronic Proximal Axonopathy in Rats is Associated With Long-Standing Neurofilament Depletion in Neuromuscular Junctions and Behavioral Deficits

Soler-Martín

Boadas-Vaello

Verdú

et al. 2014

J Neuropathol Exp Neurol

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In rodents exposed to 3,3'-iminodipropionitrile (IDPN), neurofilaments (NFs) accumulate in swollen proximal axon segments; this also occurs in motor neurons of patients with amyotrophic lateral sclerosis. We hypothesized that early loss of NFs in neuromuscular junctions (NMJs) in IDPN proximal neuropathy would result in neuromuscular dysfunction and lead to neuromuscular detachment. Adult male rats were given 0 or 15 mmol/L IDPN in drinking water for up to 1 year. The IDPN-exposed rats dragged their tails and had impaired endurance in a grip test. Neuromuscular junctions and distal axons were examined in the levator auris longus muscle after 3, 6, 9, and 12 months. Neuromuscular junctions showed a progressive reduction in NF immunolabeling, which became undetectable in up to 70% of the NMJs after 12 months. Neurofilament labeling was also reduced in preterminal axons and in a more proximal axon level within the muscle. Triple-label analysis with antisyntaxin demonstrated that the terminals remained in place and usually contained a few minute NF bundles. Electron microscopy revealed the disappearance of terminal NFs, reduced content in synaptic vesicles, and accumulation of multilamellar bodies, but scant degeneration. Thus, IDPN proximal neurofilamentous axonopathy is associated with NF depletion in motor terminals; motor weakness and structural changes in the NMJs suggest impaired synaptic function despite long-term preservation of the NMJs.

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“…Hence, research has focused on investigating the mechanisms of motoneuron cell death (de Carvalho et al, 2014). In addition, there is growing evidence indicating that alterations of NMJs and/or the skeletal muscle itself affect the pathogenic process in amyotrophic lateral sclerosis (ALS) (Miller et al, 2006;Murray et al, 2010;Wong and Martin, 2010).…”

Section: Introductionmentioning

confidence: 99%

Formation and characterisation of neuromuscular junctions between hiPSC derived motoneurons and myotubes

Demestre

Orth

Föhr³

et al. 2015

Stem Cell Research

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Striated skeletal muscle cells from humans represent a valuable source for in vitro studies of the motoric system as well as for pathophysiological investigations in the clinical settings. Myoblasts can readily be grown from human muscle tissue. However, if muscle tissue is unavailable, myogenic cells can be generated from human induced pluripotent stem cells (hiPSCs) preferably without genetic engineering. Our study aimed to optimize the generation of hiPSCs derived myogenic cells by employing selection of CD34 positive cells and followed by distinct, stepwise culture conditions. Following the expansion of CD34 positive single cells under myogenic cell culture conditions, serum deprived myoblast-like cells finally fused and formed multinucleated striated myotubes that expressed a set of key markers for muscle differentiation. In addition, these myotubes contracted upon electrical stimulation, responded to acetylcholine (Ach) and were able to generate action potentials. Finally, we co-cultured motoneurons and myotubes generated from identical hiPSCs cell lines. We could observe the early aggregation of acetylcholine receptors in muscle cells of immature co-cultures. At later stages, we identified and characterised mature neuromuscular junctions (NMJs). In summary, we describe here the successful generation of an iPS cell derived functional cellular system consisting of two distinct communicating cells types. This in vitro co-culture system could therefore contribute to research on diseases in which the motoneurons and the NMJ are predominantly affected, such as in amyotrophic lateral sclerosis or spinal muscular atrophy.

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Review: Neuromuscular synaptic vulnerability in motor neurone disease: amyotrophic lateral sclerosis and spinal muscular atrophy

Cited by 32 publications

References 198 publications

Morphological and functional changes in innervation of a fast forelimb muscle in SOD1-G85R mice

Morphological and functional changes in innervation of a fast forelimb muscle in SOD1-G85R mice

Chronic Proximal Axonopathy in Rats is Associated With Long-Standing Neurofilament Depletion in Neuromuscular Junctions and Behavioral Deficits

Formation and characterisation of neuromuscular junctions between hiPSC derived motoneurons and myotubes

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