Loss of exosomes in progranulin-associated frontotemporal dementia

详细信息    查看全文

• 作者：Luisa Benussi^a ; ¹ ; Miriam Ciani^a ; ¹ ; Elisa Tonoli^a ; Michela Morbin^b ; Luisa Palamara^b ; Diego Albani^c ; Federica Fusco^c ; Gianluigi Forloni^c ; Michela Glionna^a ; Monika Baco^a ; Anna Paterlini^a ; Silvia Fostinelli^a ; Benedetta Santini^d ; Elisabetta Galbiati^d ; Paola Gagni^e ; Marina Cretich^e ; Giuliano Binetti^a ; Fabrizio Tagliavini^b ; Davide Prosperi^d ; Marcella Chiari^e ; Roberta Ghidoni^a ; ^{rghidoni@fatebenefratelli.eu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Progranulin ; GRN ; Null mutations ; Human primary fibroblasts ; Exosomes ; Extracellular vesicles
• 刊名：Neurobiology of Aging
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：40
• 期：Complete
• 页码：41-49
• 全文大小：1337 K

文摘

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.