Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/57895

TitleNeuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures
Author(s)Miranda, André Miguel Lopes
Lasiecka, Zofia M.
Xu, Yimeng
Neufeld, Jessi
Shahriar, Sanjid
Simoes, Sabrina
Chan, Robin B.
Oliveira, Tiago Gil
Small, Scott A.
Di Paolo, Gilbert
KeywordsAmyloid beta-Protein Precursor
Animals
Autophagy
Biomarkers
Cell Line, Tumor
Class III Phosphatidylinositol 3-Kinases
Exosomes
HEK293 Cells
Humans
Lipids
Lysophospholipids
Lysosomes
Mice, Inbred C57BL
Mice, Knockout
Monoglycerides
Neurodegenerative Diseases
Neurons
Peptide Fragments
Phosphatidylinositol Phosphates
Issue dateJan-2018
PublisherNature Research
JournalNature Communications
CitationMiranda, A. M., Lasiecka, Z. M., Xu, Y., Neufeld, J., et. al.(2018). Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures. Nature communications, 9(1), 291
Abstract(s)Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders.
TypeArticle
URIhttp://hdl.handle.net/1822/57895
DOI10.1038/s41467-017-02533-w
ISSN2041-1723
e-ISSN2041-1723
Publisher versionhttps://www.nature.com/articles/s41467-017-02533-w
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee


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