Hypoglossal Motor Neuron Death Via Intralingual CTB–saporin (CTB–SAP) Injections Mimic Aspects of Amyotrophic Lateral Sclerosis (ALS) Related to Dysphagia

Lind, Lori A; Murphy, Erika R.; Lever, Teresa E.; Nichols, Nicole L.

doi:10.1016/j.neuroscience.2018.08.026

Cited by 17 publications

(39 citation statements)

References 51 publications

(90 reference statements)

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“…In close similarity to our model, other authors have proposed rodent models, where defined, small subpopulations of MNs have been removed by using CTB-Sap injection to mimic different aspects of ALS pathogenesis separately from each other. For instance, intrapleural injection can be used to mimic respiratory dysfunctions [60,61,62], and also to study respiratory plasticity after motoneuron depletion, without the concurrent participation of other confounding factors that are present in ALS models and patients [62]. Similarly, injecting CTB-Sap in the tongue muscles represents a simple model of dysphagia, which is another typical symptom of bulbar ALS [61].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, intrapleural injection can be used to mimic respiratory dysfunctions [60,61,62], and also to study respiratory plasticity after motoneuron depletion, without the concurrent participation of other confounding factors that are present in ALS models and patients [62]. Similarly, injecting CTB-Sap in the tongue muscles represents a simple model of dysphagia, which is another typical symptom of bulbar ALS [61]. The comparison between such a reductionist model and a more complex disease model would help to define the links between causes and their effects, avoiding the inclusion of too many confounding factors in the experimental setting.…”

Section: Discussionmentioning

confidence: 99%

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Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss

Gulino

Vicario

Giunta

et al. 2019

IJMS

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Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. Although motoneuronal loss is the critical hallmark of ALS given their specific vulnerability, other cell populations, including muscle and glial cells, are involved in disease onset and progression, but unraveling their specific role and crosstalk requires further investigation. In particular, little is known about the plastic changes of the degenerating motor system. These spontaneous compensatory processes are unable to halt the disease progression, but their elucidation and possible use as a therapeutic target represents an important aim of ALS research. Genetic animal models of disease represent useful tools to validate proven hypotheses or to test potential therapies, and the conception of novel hypotheses about ALS causes or the study of pathogenic mechanisms may be advantaged by the use of relatively simple in vivo models recapitulating specific aspects of the disease, thus avoiding the inclusion of too many confounding factors in an experimental setting. Here, we used a neurotoxic model of spinal motoneuron depletion induced by injection of cholera toxin-B saporin in the gastrocnemius muscle to investigate the possible occurrence of compensatory changes in both the muscle and spinal cord. The results showed that, following the lesion, the skeletal muscle became atrophic and displayed electromyographic activity similar to that observed in ALS patients. Moreover, the changes in muscle fiber morphology were different from that observed in ALS models, thus suggesting that some muscular effects of disease may be primary effects instead of being simply caused by denervation. Notably, we found plastic changes in the surviving motoneurons that can produce a functional restoration probably similar to the compensatory changes occurring in disease. These changes could be at least partially driven by glutamatergic signaling, and astrocytes contacting the surviving motoneurons may support this process.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss

Gulino

Vicario

Giunta

et al. 2019

IJMS

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“…We also assessed a toxin-based model of motoneuronal depletion established using CTB-Sap [ 14 , 26 , 27 ], which selectively targets axon terminals and kills motoneurons by retrograde suicide transport [ 28 , 29 ], thus inducing both muscular denervation and behavioural impairment of motor performance. Our reductionist in vivo model of motoneuronal disorders showed functional deficits and electromyographic signs typical of both transgenic ALS mouse model and human ALS patients [ 30 – 32 ].…”

Section: Discussionmentioning

confidence: 99%

Increased expression of connexin 43 in a mouse model of spinal motoneuronal loss

Spitale

Vicario

Rosa

et al. 2020

Aging

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Amyotrophic lateral sclerosis (ALS) is one of the most common motoneuronal disease, characterized by motoneuronal loss and progressive paralysis. Despite research efforts, ALS remains a fatal disease, with a survival of 2-5 years after disease onset. Numerous gene mutations have been correlated with both sporadic (sALS) and familiar forms of the disease, but the pathophysiological mechanisms of ALS onset and progression are still largely uncertain. However, a common profile is emerging in ALS pathological features, including misfolded protein accumulation and a cross-talk between neuroinflammatory and degenerative processes. In particular, astrocytes and microglial cells have been proposed as detrimental influencers of perineuronal microenvironment, and this role may be exerted via gap junctions (GJs)- and hemichannels (HCs)-mediated communications. Herein we investigated the role of the main astroglial GJs-forming connexin, Cx43, in human ALS and the effects of focal spinal cord motoneuronal depletion onto the resident glial cells and Cx43 levels. Our data support the hypothesis that motoneuronal depletion may affect glial activity, which in turn results in reactive Cx43 expression, further promoting neuronal suffering and degeneration.

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“…40,41 Neuronal tracing in this capacity has been achieved by intraperitoneal and intravenous injections for broad dispersal of CTB into the neurons of the spinal cord and brain. 42 A more targeted delivery approach that is useful for testing putative reagents, with labelling specifically of the neurons of the hypoglossal nucleus in the brainstem, has been described by intramuscular administration of protein into the tongue, 43,44 therefore, injections were carried out paralingually. C57BL/6 mice were treated with either 25 μg unlabelled CTB complexed with one of the two fluorescently-labelled Affimers (ACTA-A2-555 or ACTA-C6-555), or with one of the three individual components (5 μg ACTA or 20 μg CTB).…”

Section: Delivery Of Affimers To Motor Neuronsmentioning

confidence: 99%

Piggybacking on the Cholera Toxin: Identification of a Toxoid-binding Protein as an Approach for Targeted Delivery of Proteins to Motor Neurons

Balmforth

Haigh

Tiede

et al. 2020

Preprint

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A significant unmet need exists for the delivery of biologic drugs such as polypeptides or nucleic acids, to the central nervous system (CNS) for the treatment and understanding of neurodegenerative diseases. Naturally occurring toxoids have been considered as tools to meet this need. However, due to the complexity of tethering macromolecular drugs to toxins, and the inherent dangers of working with large quantities of recombinant toxin, no such route has been successfully exploited. Developing a method where toxoid and drug can be assembled immediately prior to in vivo administration has the potential to circumvent some of these issues. Using a phage-display screen, we identified two antibody mimetics, Anti-Cholera Toxoid Affimer (ACTA) -A2 and ACTA-C6 that non-covalently associate with the non-binding face of the cholera toxin B-subunit. In a first step toward the development of a non-viral motor neuron drug-delivery vehicle, we show that Affimers can be selectively delivered to motor neurons in vivo.

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Hypoglossal Motor Neuron Death Via Intralingual CTB–saporin (CTB–SAP) Injections Mimic Aspects of Amyotrophic Lateral Sclerosis (ALS) Related to Dysphagia

Cited by 17 publications

References 51 publications

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss

Neuromuscular Plasticity in a Mouse Neurotoxic Model of Spinal Motoneuronal Loss

Increased expression of connexin 43 in a mouse model of spinal motoneuronal loss

Piggybacking on the Cholera Toxin: Identification of a Toxoid-binding Protein as an Approach for Targeted Delivery of Proteins to Motor Neurons

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