Charcot-Marie-Tooth (CMT) diseases are the most common hereditary diseases of the peripheral nervous system. One of the most frequent, the dominant subtype CMT2A, is caused by mutations in the MFN2 gene coding for mitofusin 2, a dynamin-like GTPase located in the outer membrane of mitochondria. MFN2 is involved in several cellular processes such as the fusion of mitochondrial membranes, the transport of mitochondria along axons, and the tethering of mitochondria with endoplasmic reticulum. To date, more than 70 mutations associated with CMT2A and complicated variants of CMT2 have been described. They are mainly point mutations with dominant transmission, but recently some semidominant and recessive mutations have been reported. The understanding of the mechanisms by which the mutated forms of MFN2 lead to neurodegeneration is limited by the fact that few mouse models for CMT2A were successfully developed. As zebrafish have become useful to study many neurological and neuromuscular disorders, we decided to use this model to investigate the function of MFN2 and its role in CMT2A disease. Using the morpholino technique, we knocked down MFN2 in developing embryos, which resulted in severely motor-impaired fish in accordance with the loss of limbs motility observed in CMT2A patients. Investigations performed on the neuromuscular system of morphants demonstrated that larvae exhibit misshapen motor neurons and a reduction of the neuromuscular junction formation. As in human diseases, probably because of their incorrect innervation, muscular fibers appear hypotrophic and are reduced in diameter. Our results, validated by the rescue of morphants with human MFN2 mRNA, confirm the essential role of MFN2 in motor neuron development and suggest that the zebrafish could be a very useful tool to study in living embryos the effects of mutations identified in CMT2A patients.

MFN2 KNOCKDOWN CAUSES NEUROMUSCULAR ALTERATIONS DURING ZEBRAFISH (DANIO RERIO) DEVELOPMENT: CHARACTERIZATION AND ANALYSIS OF A NEW MODEL FOR CHARCOT-MARIE-TOOTH TYPE 2A NEUROPATHY

BERGAMIN, GIORGIA;VETTORI, ANDREA;MORO, ENRICO;VAZZA, GIOVANNI;TISO, NATASCIA;ARGENTON, FRANCESCO;MOSTACCIUOLO, MARIA LUISA
2011

Abstract

Charcot-Marie-Tooth (CMT) diseases are the most common hereditary diseases of the peripheral nervous system. One of the most frequent, the dominant subtype CMT2A, is caused by mutations in the MFN2 gene coding for mitofusin 2, a dynamin-like GTPase located in the outer membrane of mitochondria. MFN2 is involved in several cellular processes such as the fusion of mitochondrial membranes, the transport of mitochondria along axons, and the tethering of mitochondria with endoplasmic reticulum. To date, more than 70 mutations associated with CMT2A and complicated variants of CMT2 have been described. They are mainly point mutations with dominant transmission, but recently some semidominant and recessive mutations have been reported. The understanding of the mechanisms by which the mutated forms of MFN2 lead to neurodegeneration is limited by the fact that few mouse models for CMT2A were successfully developed. As zebrafish have become useful to study many neurological and neuromuscular disorders, we decided to use this model to investigate the function of MFN2 and its role in CMT2A disease. Using the morpholino technique, we knocked down MFN2 in developing embryos, which resulted in severely motor-impaired fish in accordance with the loss of limbs motility observed in CMT2A patients. Investigations performed on the neuromuscular system of morphants demonstrated that larvae exhibit misshapen motor neurons and a reduction of the neuromuscular junction formation. As in human diseases, probably because of their incorrect innervation, muscular fibers appear hypotrophic and are reduced in diameter. Our results, validated by the rescue of morphants with human MFN2 mRNA, confirm the essential role of MFN2 in motor neuron development and suggest that the zebrafish could be a very useful tool to study in living embryos the effects of mutations identified in CMT2A patients.
Journal of the Peripheral Nervous System
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/153895
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