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Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures
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Journal Article
Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures
2018
Overview
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.
Neurodegeneration is increasingly associated with endolysosomal and autophagy dysfunction. Here, Miranda and colleagues show that disruption of neuronal PI3P/Vps34 signaling leads to endolysosomal membrane damage and aberrant release of undigested material in APP-CTF- and BMP-positive exosomes.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
1-Phosphatidylinositol 3-kinase
/ 101/58
/ 13/1
/ 13/106
/ 14/19
/ 64/60
/ 82/29
/ 82/51
/ Amyloid beta-Protein Precursor - chemistry
/ Amyloid beta-Protein Precursor - metabolism
/ Animals
/ Class III Phosphatidylinositol 3-Kinases - genetics
/ Class III Phosphatidylinositol 3-Kinases - metabolism
/ Exosomes
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Lipids
/ Lysophospholipids - metabolism
/ Mutation
/ Neurodegenerative Diseases - diagnosis
/ Neurodegenerative Diseases - metabolism
/ Peptide Fragments - metabolism
/ Phosphatidylinositol Phosphates - metabolism
/ Proteins
/ Science
