title: Loss of exosomes in progranulin-associated frontotemporal dementia.
abstract: Many cells of the nervous system have been shown to release exosomes, a subclass of secreted vesicles of endosomal origin capable of transferring biomolecules among cells: this transfer modality represents a novel physiological form of intercellular communication between neural cells. Herein, we demonstrated that progranulin (PGRN), a protein targeted to the classical secretory pathway, is also secreted in association with exosomes by human primary fibroblasts. Moreover, we demonstrated that null mutations in the progranulin gene (GRN), a major cause of frontotemporal dementia, strongly reduce the number of released exosomes and alter their composition. In vitro GRN silencing in SHSY-5Y cells confirmed a role of PGRN in the control of exosome release. It is believed that depletion of PGRN in the brain might cause neurodegeneration in GRN-associated frontotemporal dementia. We demonstrated that, along with shortage of the circulating PGRN, GRN null mutations alter intercellular communication. Thus, a better understanding of the role played by exosomes in GRN-associated neurodegeneration is crucial for the development of novel therapies for these diseases.
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ciani
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tonoli
authors.affiliation: Division of Neuropathology and Neurology 5, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.affiliation: Division of Neuropathology and Neurology 5, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Palamara
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Albani
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Fusco
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Glionna
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy.
authors.forename: Monika
authors.initials: M
authors.lastname: Baco
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Paterlini
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fostinelli
authors.affiliation: NanoBioLab, Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milano, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Santini
authors.affiliation: NanoBioLab, Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Galbiati
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Chimica del Riconoscimento Molecolare, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Gagni
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Chimica del Riconoscimento Molecolare, Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Cretich
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Binetti
authors.affiliation: Division of Neuropathology and Neurology 5, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: NanoBioLab, Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milano, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Prosperi
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Chimica del Riconoscimento Molecolare, Milano, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Chiari
authors.affiliation: Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy. Electronic address: rghidoni@fatebenefratelli.eu.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
mesh_terms: D000368:Aged; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D000077153:Progranulins
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins
keywords: Exosomes; Extracellular vesicles; GRN; Human primary fibroblasts; Null mutations; Progranulin