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.

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B / Colecchia, David; Stasi, Mariangela; Leonardi, Margherita; Manganelli, Fiore; Nolano, Maria; Veneziani, Bianca Maria; Santoro, Lucio; Eskelinen, Eeva-liisa; Chiariello, Mario; Bucci, Cecilia. - In: AUTOPHAGY. - ISSN 1554-8627. - 14:6(2018), pp. 930-941. [10.1080/15548627.2017.1388475]

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

Manganelli, Fiore;Nolano, Maria;Veneziani, Bianca Maria;Santoro, Lucio;Chiariello, Mario;Bucci, Cecilia
2018

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 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.
2018
Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B / Colecchia, David; Stasi, Mariangela; Leonardi, Margherita; Manganelli, Fiore; Nolano, Maria; Veneziani, Bianca Maria; Santoro, Lucio; Eskelinen, Eeva-liisa; Chiariello, Mario; Bucci, Cecilia. - In: AUTOPHAGY. - ISSN 1554-8627. - 14:6(2018), pp. 930-941. [10.1080/15548627.2017.1388475]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/693080
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