Overexpression of an ALS-associated FUS mutation in <i>C. elegans</i> disrupts NMJ morphology and leads to defective neuromuscular transmission

Markert, Sebastian M.; Skoruppa, Michael Peter; Yu, Bin; Mulcahy, Ben; Zhen, Mei; Gao, Shangbang; Sendtner, Michael; Stigloher, Christian

doi:10.1242/bio.055129

Cited by 28 publications

(18 citation statements)

References 66 publications

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“…The NMJ plays an essential role in transmitting the electrical signals generated by the presynaptic motor neuron to the postsynaptic, excitable myofiber that results in muscle contraction. Consistent with the basic biological tenet this form is inextricably linked with function, changes in neuromuscular activity induce morphological adaptations of the NMJ (Fahim, 1997; Markert et al., 2020; Ng & Ljubicic, 2020). Indeed, it has been reported that increased neuromuscular activity, such as exercise, significantly expands the dimensions of both pre‐ and postsynaptic components of the NMJ (Deschenes et al., 1993; Fahim, 1997), while disuse, whether complete or subtotal, typically results in diminution of the NMJ (Deschenes et al., 2006; Wilson & Deschenes, 2005).…”

Section: Discussionmentioning

confidence: 83%

Sensitivity of subcellular components of neuromuscular junctions to decreased neuromuscular activity

Deschenes

Trebelhorn

High

et al. 2021

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Muscle unloading imparts subtotal disuse on the neuromuscular system resulting in reduced performance capacity. This loss of function, at least in part, can be attributed to disruptions at the neuromuscular junction (NMJ). However, research has failed to document morphological remodeling of the NMJ with short term muscle unloading. Here, rather than quantifying cellular components of the NMJ, we examined subcellular active zone responses to 2 weeks of unloading in male Wistar rats. It was revealed that in the plantaris, but not the soleus muscles, unloading elicited significant (P ≤ 0.05) decrements in active zone staining as measured by Bassoon, and calcium channel expression. It was also discovered that unloading decreased the area of calcium channels staining relative to active zone areas of staining suggesting potential interference in the ability of calcium influx to trigger the release of vesicles docked at the active zone. Post‐synaptic adaptations of the motor endplate were not evident. This presynaptic subcellular size reduction was not associated with atrophy of the underlying plantaris muscle fibers, although atrophy of the weight‐bearing soleus fibers, where no subcellular remodeling was evident, was noted. These results suggest that the active zone is highly sensitive to alterations in neuromuscular activity, and that morphological adaptation of excitatory and contractile components of the NMJ can occur independently of each other.

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Section: Discussionmentioning

confidence: 83%

Sensitivity of subcellular components of neuromuscular junctions to decreased neuromuscular activity

Deschenes

Trebelhorn

High

et al. 2021

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“…Hence, the mutation leads to locomotion defects and neuronal transmission impairment ( 55 , 58 ). Also, transgenic expression of mutant FUS shows mislocalized cytoplasmic aggregation of this protein and is associated with reduced transmission of synaptic vesicles from neurons to muscles at the neuromuscular junction ( 55 , 58 , 62 ). Moreover, expression of mutant TDP-43 in GABAergic motor neurons causes neurodegeneration, synapses impairment, progressive age-dependent motor defect, and increased endoplasmic reticulum (ER) stress ( 55 , 58 ).…”

Section: Als In Vivo Modeling Platformsmentioning

confidence: 99%

Organ on a Chip: A Novel in vitro Biomimetic Strategy in Amyotrophic Lateral Sclerosis (ALS) Modeling

et al. 2022

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Amyotrophic lateral sclerosis is a pernicious neurodegenerative disorder that is associated with the progressive degeneration of motor neurons, the disruption of impulse transmission from motor neurons to muscle cells, and the development of mobility impairments. Clinically, muscle paralysis can spread to other parts of the body. Hence it may have adverse effects on swallowing, speaking, and even breathing, which serves as major problems facing these patients. According to the available evidence, no definite treatment has been found for amyotrophic lateral sclerosis (ALS) that results in a significant outcome, although some pharmacological and non-pharmacological treatments are currently applied that are accompanied by some positive effects. In other words, available therapies are only used to relieve symptoms without any significant treatment effects that highlight the importance of seeking more novel therapies. Unfortunately, the process of discovering new drugs with high therapeutic potential for ALS treatment is fraught with challenges. The lack of a broad view of the disease process from early to late-stage and insufficiency of preclinical studies for providing validated results prior to conducting clinical trials are other reasons for the ALS drug discovery failure. However, increasing the combined application of different fields of regenerative medicine, especially tissue engineering and stem cell therapy can be considered as a step forward to develop more novel technologies. For instance, organ on a chip is one of these technologies that can provide a platform to promote a comprehensive understanding of neuromuscular junction biology and screen candidate drugs for ALS in combination with pluripotent stem cells (PSCs). The structure of this technology is based on the use of essential components such as iPSC- derived motor neurons and iPSC-derived skeletal muscle cells on a single miniaturized chip for ALS modeling. Accordingly, an organ on a chip not only can mimic ALS complexities but also can be considered as a more cost-effective and time-saving disease modeling platform in comparison with others. Hence, it can be concluded that lab on a chip can make a major contribution as a biomimetic micro-physiological system in the treatment of neurodegenerative disorders such as ALS.

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“…High pressure freezing chamber sandwiches were opened to allow better penetration during freeze substitution. Samples were incubated as described previously (Markert et al, 2020;Stigloher et al, 2011). Briefly, samples were kept in anhydrous acetone containing 0.1% tannic acid and 0.5% glutaraldehyde for 20h at -90°C.…”

Section: Freeze Substitutionmentioning

confidence: 99%

Ultrastructural analysis of wildtype and RIM1α knock-out active zones in a large cortical synapse

Lichter

Paul

Pauli

et al. 2022

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SummaryRab3A-interacting molecule (RIM) is crucial for fast Ca2+-triggered synaptic vesicle (SV) release in presynaptic active zones (AZ). While loss of RIM1α impairs long-term plasticity at hippocampal giant mossy fiber boutons (MFB), it remains unclear how AZ ultrastructure is altered. We investigated MFB AZ architecture in 3D using electron tomography of rapid cryo-immobilized acute brain slices in RIM1α-/- and wild-type mice. In RIM1α-/-, AZs are larger with increased synaptic cleft heights and with a three-fold reduced number of tightly docked SVs (0-2nm). The distance of tightly docked SVs to the AZ center is increased from 110 to 195 nm, and the width of their electron dense material between outer SV membrane and AZ membrane is reduced. Furthermore, the SV pool in RIM1α-/- is more heterogeneous. Thus, RIM1α, beside its role in tight SV docking, is crucial for synaptic architecture and vesicle pool organization in MFBs.

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Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission

Cited by 28 publications

References 66 publications

Sensitivity of subcellular components of neuromuscular junctions to decreased neuromuscular activity

Sensitivity of subcellular components of neuromuscular junctions to decreased neuromuscular activity

Organ on a Chip: A Novel in vitro Biomimetic Strategy in Amyotrophic Lateral Sclerosis (ALS) Modeling

Ultrastructural analysis of wildtype and RIM1α knock-out active zones in a large cortical synapse

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