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

André M. Miranda, Zofia M. Lasiecka, Yimeng Xu, Jessi Neufeld, Sanjid Shahriar, Sabrina Simoes, Robin B. Chan, Tiago Gil Oliveira, Scott A. Small and Gilbert Di Paolo ()
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André M. Miranda: Columbia University Medical Center
Zofia M. Lasiecka: Columbia University Medical Center
Yimeng Xu: Columbia University Medical Center
Jessi Neufeld: Columbia University Medical Center
Sanjid Shahriar: Columbia University Medical Center
Sabrina Simoes: Columbia University Medical Center
Robin B. Chan: Columbia University Medical Center
Tiago Gil Oliveira: University of Minho
Scott A. Small: Columbia University Medical Center
Gilbert Di Paolo: Columbia University Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02533-w

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