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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)930-941
Number of pages12
JournalAutophagy
Volume14
Issue number6
DOIs
Publication statusPublished - 2018

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    Colecchia, D., Stasi, M., Leonardi, M., Manganelli, F., Nolano, M., Veneziani, B. M., Santoro, L., Eskelinen, E-L., Chiariello, M., & Bucci, C. (2018). Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B. Autophagy, 14(6), 930-941. https://doi.org/10.1080/15548627.2017.1388475