Voltage-gated sodium channels (VGSCs) are multimeric protein complexes formed by one alpha subunit and one or two accessory beta subunits. These channels are responsible for the generation of inward Na+ currents. A small fraction of these currents is represented by a non-inactivating component, the persistent Na+ current or INaP. Recent evidence suggests that VGSCs and INaP are important not only in the regulation of excitable cell electrical properties but also in promoting neuronal development and neurite outgrowth. Interestingly, both VGSCs and INaP alterations and defects in neuron morphology and neurite outgrowth were reported in Amyotrophic Lateral Sclerosis (ALS). ALS is fatal neurodegenerative disease causing muscle denervation and wasting, paralysis and death of the patient usually within 5 years from diagnosis. We previously observed defects in motor axons morphology together with motor- and interneuron INaP -dependent hyperexcitability in a zebrafish model expressing an ALS-associated mutant SOD1. To investigate the role of VGSCs related currents in neuronal differentiation and their possible role in the pathogenesis of ALS, we took advantage of the NSC34 cell line, often used as an in vitro model to study motoneuron diseases. We used two NSC34 populations: cells stably expressing G93A mutant SOD1 and cells defective in the expression of the Vesicle Associated Membrane Protein (VAMP)-Associated Protein B (VAPB). We analyzed VGSCs expression and localization through molecular, biochemical and imaging approaches and found interesting correlations and differences between VGSCs expression, localization, function and neurite outgrowth in wild-type and mutant cells. Our study thus confirms the proposed role of VGSCs in tuning neuronal differentiation with a precise temporal pattern. Disruption of this pattern might have relevant implications in ALS pathogenesis.

The role of Voltage-Gated Sodium Channels in neuronal differentiation and their contribution to Amyotrophic Lateral Sclerosis pathogenesis / M. Francolini, G. Maiellano, D. Scalzo, L. Scandella, M.N. Colombo. ((Intervento presentato al 20. convegno Congresso Nazionale dell’Associazione Italiana di Biologia e Genetica tenutosi a Roma nel 2022.

The role of Voltage-Gated Sodium Channels in neuronal differentiation and their contribution to Amyotrophic Lateral Sclerosis pathogenesis

M. Francolini
Primo
;
G. Maiellano
Secondo
;
D. Scalzo;L. Scandella
Penultimo
;
M.N. Colombo
Ultimo
2022

Abstract

Voltage-gated sodium channels (VGSCs) are multimeric protein complexes formed by one alpha subunit and one or two accessory beta subunits. These channels are responsible for the generation of inward Na+ currents. A small fraction of these currents is represented by a non-inactivating component, the persistent Na+ current or INaP. Recent evidence suggests that VGSCs and INaP are important not only in the regulation of excitable cell electrical properties but also in promoting neuronal development and neurite outgrowth. Interestingly, both VGSCs and INaP alterations and defects in neuron morphology and neurite outgrowth were reported in Amyotrophic Lateral Sclerosis (ALS). ALS is fatal neurodegenerative disease causing muscle denervation and wasting, paralysis and death of the patient usually within 5 years from diagnosis. We previously observed defects in motor axons morphology together with motor- and interneuron INaP -dependent hyperexcitability in a zebrafish model expressing an ALS-associated mutant SOD1. To investigate the role of VGSCs related currents in neuronal differentiation and their possible role in the pathogenesis of ALS, we took advantage of the NSC34 cell line, often used as an in vitro model to study motoneuron diseases. We used two NSC34 populations: cells stably expressing G93A mutant SOD1 and cells defective in the expression of the Vesicle Associated Membrane Protein (VAMP)-Associated Protein B (VAPB). We analyzed VGSCs expression and localization through molecular, biochemical and imaging approaches and found interesting correlations and differences between VGSCs expression, localization, function and neurite outgrowth in wild-type and mutant cells. Our study thus confirms the proposed role of VGSCs in tuning neuronal differentiation with a precise temporal pattern. Disruption of this pattern might have relevant implications in ALS pathogenesis.
2022
Settore BIO/11 - Biologia Molecolare
The role of Voltage-Gated Sodium Channels in neuronal differentiation and their contribution to Amyotrophic Lateral Sclerosis pathogenesis / M. Francolini, G. Maiellano, D. Scalzo, L. Scandella, M.N. Colombo. ((Intervento presentato al 20. convegno Congresso Nazionale dell’Associazione Italiana di Biologia e Genetica tenutosi a Roma nel 2022.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1035773
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