Alteration of the late endocytic pathway in Charcot-Marie-Tooth type 2B disease
| Autor: | Roberta Romano, Eeva-Liisa Eskelinen, Cristina Rivellini, Raffaella Beli, Fiore Manganelli, Stefano C. Previtali, Rossana Tonlorenzi, Maria De Luca, Maria Nolano, Cecilia Bucci, Lucio Santoro |
|---|---|
| Přispěvatelé: | Romano, Roberta, Rivellini, Cristina, De Luca, Maria, Tonlorenzi, Rossana, Beli, Raffaella, Manganelli, Fiore, Nolano, Maria, Santoro, Lucio, Eskelinen, Eeva-Liisa, Previtali, Stefano C, Bucci, Cecilia, Romano, R., Rivellini, C., De Luca, M., Tonlorenzi, R., Beli, R., Manganelli, F., Nolano, M., Santoro, L., Eskelinen, E. -L., Previtali, S. C., Bucci, C., Molecular and Integrative Biosciences Research Programme, Autophagy, Biochemistry and Biotechnology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
rac1 GTP-Binding Protein
MILD COGNITIVE IMPAIRMENT Endocytic cycle Cathepsin D UP-REGULATION EARLY ENDOSOME 0302 clinical medicine Cell Movement Charcot-Marie-Tooth Disease RNA Small Interfering NEURONS Cells Cultured Migration 0303 health sciences Endocytosi RAB7A Neurodegeneration RAB7 MUTATION Cellular Reprogramming Lysosome Endocytosis 3. Good health Cell biology ErbB Receptors medicine.anatomical_structure Matrix Metalloproteinase 2 Molecular Medicine RNA Interference Original Article RAC1 GROWTH-FACTOR Sensory Receptor Cells Neurite PROTEINS EGFR Induced Pluripotent Stem Cells Biology Polymorphism Single Nucleotide 03 medical and health sciences Cellular and Molecular Neuroscience Downregulation and upregulation medicine Humans NUCLEOTIDE EXCHANGE Molecular Biology 030304 developmental biology Pharmacology Laminopathies rab7 GTP-Binding Proteins Cell Biology Fibroblasts CATHEPSIN-D medicine.disease Cathepsins rab GTP-Binding Proteins Proteolysis PLASMA-MEMBRANE 1182 Biochemistry cell and molecular biology Lysosomes 030217 neurology & neurosurgery |
| Zdroj: | Cellular and Molecular Life Sciences |
| Popis: | The small GTPase RAB7A regulates late stages of the endocytic pathway and plays specific roles in neurons, controlling neurotrophins trafficking and signaling, neurite outgrowth and neuronal migration. Mutations in the RAB7A gene cause the autosomal dominant Charcot–Marie–Tooth type 2B (CMT2B) disease, an axonal peripheral neuropathy. As several neurodegenerative diseases are caused by alterations of endocytosis, we investigated whether CMT2B-causing mutations correlate with changes in this process. To this purpose, we studied the endocytic pathway in skin fibroblasts from healthy and CMT2B individuals. We found higher expression of late endocytic proteins in CMT2B cells compared to control cells, as well as higher activity of cathepsins and higher receptor degradation activity. Consistently, we observed an increased number of lysosomes, accompanied by higher lysosomal degradative activity in CMT2B cells. Furthermore, we found increased migration and increased RAC1 and MMP-2 activation in CMT2B compared to control cells. To validate these data, we obtained sensory neurons from patient and control iPS cells, to confirm increased lysosomal protein expression and lysosomal activity in CMT2B-derived neurons. Altogether, these results demonstrate that in CMT2B patient-derived cells, the endocytic degradative pathway is altered, suggesting that higher lysosomal activity contributes to neurodegeneration occurring in CMT2B. Electronic supplementary material The online version of this article (10.1007/s00018-020-03510-1) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|