Abstracts of the Meeting of the Associazione Italiana Sistema Nervoso Periferico April 28–30, 2011 Bologna, Italy

Charcot-Marie-Tooth (CMT) diseases are the mostcommon hereditary diseases of the peripheral nervoussystem. One of the most frequent, the dominant subtype CMT2A, is caused by mutations in the MFN2gene coding for mitofusin 2, a dynamin-like GTPaselocated in the outer membrane of mitochondria. MFN2is involved in several cellular processes such as thefusion of mitochondrial membranes, the transportof mitochondria along axons, and the tethering ofmitochondria with endoplasmic reticulum. To date,more than 70 mutations associated with CMT2A andcomplicated variants of CMT2 have been described.They are mainly point mutations with dominanttransmission, but recently some semidominantand recessive mutations have been reported. Theunderstanding of the mechanisms by which themutated forms of MFN2 lead to neurodegenerationis limited by the fact that few mouse models forCMT2A were successfully developed. As zebrafishhave become useful to study many neurological andneuromuscular disorders, we decided to use thismodel to investigate the function of MFN2 and its rolein CMT2A disease. Using the morpholino technique,we knocked down MFN2 in developing embryos,which resulted in severely motor-impaired fish inaccordance with the loss of limbs motility observedin CMT2A patients. Investigations performed on theneuromuscular system of morphants demonstratedthat larvae exhibit misshapen motor neurons and areduction of the neuromuscular junction formation. Asin human diseases, probably because of their incorrectinnervation, muscular fibers appear hypotrophic andare reduced in diameter. Our results, validated bythe rescue of morphants with human MFN2 mRNA,confirm the essential role of MFN2 in motor neurondevelopment and suggest that the zebrafish could bea very useful tool to study in living embryos the effectsof mutations identified in CMT2A patients