Autophagy and Lysosomal Functionality in CMT2B Fibroblasts Carrying the RAB7K126R Mutation

Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by five mutations in the RAB7A gene. Autophagy and late endocytic trafficking were already characterized in CMT2B. Indeed, impairment of autophagy and an increase in lysosomal degradative activity were foun...

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Published in:Cells (Basel, Switzerland) Switzerland), 2022-01, Vol.11 (3), p.496
Main Authors: Romano, Roberta, Del Fiore, Victoria Stefania, Saveri, Paola, Palamà, Ilaria Elena, Pisciotta, Chiara, Pareyson, Davide, Bucci, Cecilia, Guerra, Flora
Format: Article
Language:English
Subjects:
Antibodies
Autophagy
Biosynthesis
Biotechnology
Bone surgery
Charcot-Marie-Tooth
Charcot-Marie-Tooth disease
Epidermal growth factor receptors
Experiments
Fibroblasts
Immunofluorescence
lipid droplets
lipophagy
Localization
lysosome
Mutants
Mutation
Peripheral neuropathy
Phenotypes
Plasmids
Proteins
RAB7A
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Summary:Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by five mutations in the RAB7A gene. Autophagy and late endocytic trafficking were already characterized in CMT2B. Indeed, impairment of autophagy and an increase in lysosomal degradative activity were found in cells expressing the mutant proteins. Recently, we described a novel RAB7 mutation associated with predominantly motor CMT2 and impaired EGFR trafficking. With the aim to analyze the autophagy process and lysosomal activity in CMT2B fibroblasts carrying the p.K126R RAB7 novel mutation and to investigate further the causes of the different phenotype, we have performed Western blot, immunofluorescence and cytometric analyses monitoring autophagic markers and endocytic proteins. Moreover, we investigated lipophagy by analyzing accumulation of lipid droplets and their co-localization with endolysosomal degradative compartments. We found that cells expressing the RAB7K126R mutant protein were characterized by impairment of autophagy and lipophagy processes and by a moderate increase in lysosomal activity compared to the previously studied cells carrying the RAB7V162M mutation. Thus, we concluded that EGFR trafficking alterations and a moderate increase in lysosomal activity with concomitant impairment of autophagy could induce the specific predominantly motor phenotype observed in K126R patients.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11030496