Journal Article

Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures

Simoes, Sabrina, Miranda, André M., Neufeld, Jessi, Small, Scott A., Xu, Yimeng, Lasiecka, Zofia M., Chan, Robin B., Di Paolo, Gilbert, Oliveira, Tiago Gil, Shahriar, Sanjid

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 Research,Nature Portfolio
• Subject: 1-Phosphatidylinositol 3-kinase / 101/58 / 13/1 / 13/106 / 14/19 / 631/378/1689/1602 / 631/378/1689/364 / 631/80/304 / 631/80/313/1624 / 64/60 / 82/29 / 82/51 / Alzheimer's disease / Amyloid beta-Protein Precursor - chemistry / Amyloid beta-Protein Precursor - metabolism / Amyloid precursor protein / Animals / Autophagy / Autophagy - genetics / Biomarkers / Biomarkers - metabolism / Bone morphogenetic proteins / Cell Line / Cell Line, Tumor / Ciências Médicas / Class III Phosphatidylinositol 3-Kinases - genetics / Class III Phosphatidylinositol 3-Kinases - metabolism / Disorders / Exosomes / Exosomes - metabolism / Experiments / Fragments / HEK293 Cells / Humanities and Social Sciences / Humans / Inbred C57BL / Kinases / Knockout / Lipid metabolism / Lipids / Lipids - analysis / Lysophospholipids / Lysophospholipids - metabolism / Lysosomes / Lysosomes - metabolism / Medicina Básica / Metabolism / Metabolites / Mice / Mice, Inbred C57BL / Mice, Knockout / Monoglycerides / Monoglycerides - metabolism / multidisciplinary / Mutation / Neurodegeneration / Neurodegenerative Diseases / Neurodegenerative Diseases - diagnosis / Neurodegenerative Diseases - metabolism / Neurons / Neurons - metabolism / Peptide Fragments / Peptide Fragments - metabolism / Phagocytosis / Phosphatidylinositol Phosphates / Phosphatidylinositol Phosphates - metabolism / Phospholipids / Protein C / Proteins / Science / Science (multidisciplinary) / Secretion / Sphingolipids / Sphingomyelin phosphodiesterase / Substrates / Tumor