2. Academic Validation
  3. Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures

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

  • Nat Commun. 2018 Jan 18;9(1):291. doi: 10.1038/s41467-017-02533-w.
André M Miranda 1 2 3 4,  Zofia M Lasiecka 1,  Yimeng Xu 1,  Jessi Neufeld 2 5,  Sanjid Shahriar 1,  Sabrina Simoes 2 5,  Robin B Chan 1 2,  Tiago Gil Oliveira 3 4,  Scott A Small 2 5,  Gilbert Di Paolo 6 7 8
Affiliations

Affiliations

  • 1 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.
  • 2 Taub Institute for Research on Alzheimer's disease and the Aging Brain, Columbia University Medical Center, New York, NY, 10032, USA.
  • 3 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, 4710-057, Portugal.
  • 4 ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, 4710-057, Portugal.
  • 5 Departments of Neurology, Columbia University Medical Center, New York, NY, 10032, USA.
  • 6 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA. dipaolo@dnli.com.
  • 7 Taub Institute for Research on Alzheimer's disease and the Aging Brain, Columbia University Medical Center, New York, NY, 10032, USA. dipaolo@dnli.com.
  • 8 Denali Therapeutics, South San Francisco, CA, 94080, USA. dipaolo@dnli.com.
PMID: 29348617 DOI: 10.1038/s41467-017-02533-w
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.

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