A1 Refereed original research article in a scientific journal
Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B
Authors: Colecchia D, Stasi M, Leonardi M, Manganelli F, Nolano M, Veneziani BM, Santoro L, Eskelinen EL, Chiariello M, Bucci C
Publisher: TAYLOR & FRANCIS INC
Publication year: 2018
Journal: Autophagy
Journal name in source: AUTOPHAGY
Journal acronym: AUTOPHAGY
Volume: 14
Issue: 6
First page : 930
Last page: 941
Number of pages: 12
ISSN: 1554-8627
DOI: https://doi.org/10.1080/15548627.2017.1388475
Self-archived copy’s web address: https://research.utu.fi/converis/portal/Publication/35809750
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 RAB7A(WT), expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7A(T22N) mutant. Consistently, both basal and starvation-induced autophagy were strongly inhibited in skin fibroblasts from a CMT2B patient carrying the RAB7A(V162M) mutation, suggesting that alteration of the autophagic flux could be responsible for neurodegeneration.
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