Published Date: November 14, 2017

Full Text Article

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B


Authors: David Colecchia, Mariangela Stasi, Margherita Leonardi, Fiore Manganelli, Maria Nolano, Bianca Maria Veneziani, Lucio Santoro, Eeva-Liisa Eskelinen, Mario Chiariello, Cecilia Bucci


Autophagy. 2018;14(6):930-941. doi: 10.1080/15548627.2017.1388475. Epub 2018 May 4.

ABSTRACT

Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. In neurons, RAB7A also controls neuronal-specific processes such as NTF (neurotrophin) trafficking and signaling, neurite outgrowth and neuronal migration. Given the involvement of macroautophagy/autophagy in several neurodegenerative diseases and considering that RAB7A is fundamental for autophagosome maturation, we investigated whether CMT2B-causing mutants affect the ability of this gene to regulate autophagy. In HeLa cells, we observed a reduced localization of all CMT2B-causing RAB7A mutants on autophagic compartments. Furthermore, compared to expression of RAB7AWT, expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7AT22N mutant. Consistently, both basal and starvation-induced autophagy were strongly inhibited in skin fibroblasts from a CMT2B patient carrying the RAB7AV162M mutation, suggesting that alteration of the autophagic flux could be responsible for neurodegeneration.

PMID: 29130394DOI: 10.1080/15548627.2017.1388475PMC: PMC6103410