Alteration of the late endocytic pathway in Charcot-Marie-Tooth type 2B disease

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dc.contributor.author Romano, Roberta
dc.contributor.author Rivellini, Cristina
dc.contributor.author De Luca, Maria
dc.contributor.author Tonlorenzi, Rossana
dc.contributor.author Beli, Raffaella
dc.contributor.author Manganelli, Fiore
dc.contributor.author Nolano, Maria
dc.contributor.author Santoro, Lucio
dc.contributor.author Eskelinen, Eeva-Liisa
dc.contributor.author Previtali, Stefano C.
dc.contributor.author Bucci, Cecilia
dc.date.accessioned 2021-06-17T11:23:02Z
dc.date.available 2021-06-17T11:23:02Z
dc.date.issued 2021
dc.identifier.citation 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 2021 , ' Alteration of the late endocytic pathway in Charcot-Marie-Tooth type 2B disease ' , Cellular and Molecular Life Sciences , vol. 78 , pp. 351–372 . https://doi.org/10.1007/s00018-020-03510-1
dc.identifier.other PURE: 158723000
dc.identifier.other PURE UUID: 43426d7b-10ef-4497-9499-6c58a3483980
dc.identifier.other WOS: 000534393400001
dc.identifier.other ORCID: /0000-0003-0006-7785/work/95669581
dc.identifier.uri http://hdl.handle.net/10138/331483
dc.description.abstract 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. en
dc.format.extent 22
dc.language.iso eng
dc.relation.ispartof Cellular and Molecular Life Sciences
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject RAB7A
dc.subject Endocytosis
dc.subject Lysosome
dc.subject RAC1
dc.subject Migration
dc.subject EGFR
dc.subject MILD COGNITIVE IMPAIRMENT
dc.subject GROWTH-FACTOR
dc.subject RAB7 MUTATION
dc.subject NUCLEOTIDE EXCHANGE
dc.subject PLASMA-MEMBRANE
dc.subject EARLY ENDOSOME
dc.subject UP-REGULATION
dc.subject CATHEPSIN-D
dc.subject PROTEINS
dc.subject NEURONS
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title Alteration of the late endocytic pathway in Charcot-Marie-Tooth type 2B disease en
dc.type Article
dc.contributor.organization Molecular and Integrative Biosciences Research Programme
dc.contributor.organization Autophagy
dc.contributor.organization Biochemistry and Biotechnology
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1007/s00018-020-03510-1
dc.relation.issn 1420-682X
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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