CoChat
Sign Up
Cited by 226

The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.

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

Miranda, André M., Lasiecka, Zofia M., Xu, Yimeng, Neufeld, Jessi, Shahriar, Sanjid, Simoes, Sabrina, Chan, Robin B., Oliveira, Tiago Gil, Small, Scott A., Di Paolo, Gilbert·2018·Nature Communications
DOI 10.1038/s41467-017-02533-wPMC PMC5773483
Open this paper in CoChat — free account

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-017-02533-w

Cites

10 of 10 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The elevation of GM3 and BMP species potentially indicates lysosomal dysfunction.

    “potentially indicating lysosomal dysfunction”

    From TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge (2020) · cites this paper as Miranda et al., 2018

    The Results section (‘Vps34 ablation in neurons alters brain exosome composition’; page unavailable) reports increased BMP levels ‘consistent with endolysosomal impairment,’ supporting the proposed link for BMP. Our copy does not report an elevation of GM3 or link GM3 to lysosomal dysfunction, so that part of the claim is unsupported. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 60

  1. Nixon, R. a. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997 (2013). · DOI · Paper page
  2. Small, S. A., Simoes-Spassov, S., Mayeux, R. & Petsko, G. A. Endosomal traffic jams represent a pathogenic hub and therapeutic target in Alzheimer’s disease. Trends Neurosci. 40, 592–602 (2017). · DOI · Paper page
  3. Abeliovich, A. & Gitler, A. D. Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature 539, 207–216 (2016). · DOI · Paper page
  4. Kao, A. W., Mckay, A., Singh, P. P., Brunet, A. & Huang, E. J. Progranulin, lysosomal regulation and neurodegenerative disease. Nat. Rev. Neurosci. 18, 325–333 (2017). · DOI
  5. Settembre, C., Fraldi, A., Medina, D. L. & Ballabio, A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell. Biol. 14, 283–296 (2013). · DOI
  6. Platt, F. M. Sphingolipid lysosomal storage disorders. Nature 510, 68–75 (2014). · DOI
  7. Karch, C. M. & Goate, A. M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77, 43–51 (2015). · DOI · Paper page
  8. Backer, J. M. The intricate regulation and complex functions of the Class III phosphoinositide 3-kinase Vps34. Biochem. J. 473, 2251–2271 (2016). · DOI
  9. Dall’Armi, C., Devereaux, K. a. & Di Paolo, G. The role of lipids in the control of autophagy. Curr. Biol. 23, R33–R45 (2013). · DOI
  10. Mccartney, A. J., Zhang, Y. & Weisman, L. S. Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance. BioEssays 36, 52–64 (2014). · DOI
  11. Wang, L., Budolfson, K. & Wang, F. Pik3c3 deletion in pyramidal neurons results in loss of synapses, extensive gliosis and progressive neurodegeneration. Neuroscience 172, 427–442 (2011). · DOI · Paper page
  12. Zhou, X. et al. Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway. Proc. Natl Acad. Sci. USA 107, 9424–9429 (2010). · DOI · Paper page
  13. Taghavi, S. et al. A clinical and molecular genetic study of 50 families with autosomal recessive parkinsonism revealed known and novel gene mutations. Mol. Neurobiol. https://doi.org/10.1007/s12035-017-0535-1 (2017). · DOI
  14. Bissig, C. & Gruenberg, J. Lipid sorting and multivesicular endosome biogenesis. Cold Spring Harb. Perspect. Biol. 5, a016816 (2013). · DOI · Paper page
  15. Bago, R. et al. Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase. Biochem. J. 463, 413–427 (2014). · DOI · Paper page
  16. Dowdle, W. E. et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat. Cell. Biol. 16, 1069–1079 (2014). · DOI · Paper page
  17. Devereaux, K. et al. Regulation of mammalian autophagy by class II and III PI 3-kinases through PI3P synthesis. PLoS ONE 8, 10–12 (2013). · DOI · Paper page
  18. Zoncu, R. et al. A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell 136, 1110–1121 (2009). · DOI
  19. Braulke, T. & Bonifacino, J. S. Sorting of lysosomal proteins. Biochim. Biophys. Acta 1793, 605–614 (2009). · DOI · Paper page
  20. Boland, B. et al. Macroautophagy is not directly involved in the metabolism of amyloid precursor protein. J. Biol. Chem. 285, 37415–37426 (2010). · DOI
  21. Katsuragi, Y., Ichimura, Y. & Komatsu, M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J. 282, 4672–4678 (2015). · DOI
  22. Kishi-Itakura, C., Koyama-Honda, I., Itakura, E. & Mizushima, N. Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells. J. Cell Sci. 127, 4984–4984 (2014). · DOI
  23. Kobayashi, T. et al. Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat. Cell. Biol. 1, 113–118 (1999). · DOI
  24. Banning, A., Tomasovic, A. & Tikkanen, R. Functional aspects of membrane association of reggie/flotillin proteins. Curr. Protein Pept. Sci. 12, 725–735 (2011). · DOI
  25. Eitan, E., Suire, C., Zhang, S. & Mattson, M. P. Impact of lysosome status on extracellular vesicle content and release. Ageing Res. Rev. 32, 65–74 (2016). · DOI
  26. Strauss, K. et al. Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann-Pick type C disease. J. Biol. Chem. 285, 26279–26288 (2010). · DOI
  27. Chivet, M. et al. Exosomes as a novel way of interneuronal communication. Biochem. Soc. Trans. 41, 241–244 (2013). · DOI
  28. Huebner, A. R. et al. Deubiquitylation of protein cargo is not an essential step in exosome formation. Mol. Cell. Proteom. 15, 1556–1571 (2016). · DOI
  29. Hessvik, N. P. et al. PIKfyve inhibition increases exosome release and induces secretory autophagy. Cell. Mol. Life. Sci. 73, 4717–4737 (2016). · DOI · Paper page
  30. Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158 (2010). · DOI · Paper page
  31. Sharples, R. A. et al. Inhibition of gamma-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB J. 22, 1469–1478 (2008). · DOI
  32. Bento, C. F. et al. Mammalian autophagy: how does it work? Annu. Rev. Biochem. 85, 685–713 (2016). · DOI
  33. Trajkovic, K. et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244–1247 (2008). · DOI
  34. Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015). · DOI · Paper page
  35. Nielsen, M. M. B. et al. Mass spectrometry imaging of biomarker lipids for phagocytosis and signalling during focal cerebral ischaemia. Sci. Rep. 6, 39571 (2016). · DOI
  36. Perez-Gonzalez, R., Gauthier, S. A., Kumar, A. & Levy, E. The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J. Biol. Chem. 287, 43108–43115 (2012). · DOI
  37. Peric, A. & Annaert, W. Early etiology of Alzheimer’s disease: tipping the balance toward autophagy or endosomal dysfunction? Acta Neuropathol. 129, 363–381 (2015). · DOI
  38. Jiang, Y. et al. Alzheimer’s-related endosome dysfunction in Down syndrome is A -independent but requires APP and is reversed by BACE-1 inhibition. Proc. Natl Acad. Sci. USA 107, 1630–1635 (2010). · DOI
  39. Kim, S. et al. Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer’s disease. Mol. Psychiatry 21, 707–716 (2016). · DOI · Paper page
  40. Petanceska, S. S. & Gandy, S. The phosphatidylinositol 3-kinase inhibitor wortmannin alters the metabolism of the Alzheimer’s amyloid precursor protein. J. Neurochem. 73, 2316–2320 (1999). · DOI
  41. Maulik, M. et al. APP overexpression in the absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer’s disease. Hum. Mol. Genet. 24, 7132–7150 (2015).
  42. Gabandé-Rodríguez, E., Boya, P., Labrador, V., Dotti, C. G. & Ledesma, M. D. High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A. Cell. Death. Differ. 21, 864–875 (2014). · DOI
  43. Blom, T. et al. LAPTM4B facilitates late endosomal ceramide export to control cell death pathways. Nat. Chem. Biol. 11, 799–806 (2015). · DOI
  44. Rodriguez-Navarro, J. A. et al. Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc. Natl Acad. Sci. USA 109, E705–E714 (2012). · DOI
  45. Li, Y. et al. The lysosomal membrane protein SCAV-3 maintains lysosome integrity and adult longevity. J. Cell. Biol. 215, 167–185 (2016). · DOI
  46. Papadopoulos, C. et al. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J. 36, 135–150 (2017). · DOI
  47. Calafate, S., Flavin, W., Verstreken, P. & Moechars, D. Loss of Bin1 promotes the propagation of Tau pathology. Cell Rep. 17, 931–940 (2016). · DOI · Paper page
  48. Levy, E. Exosomes in the diseased brain: first insights from in vivo studies. Front. Neurosci. 11, 142 (2017).
  49. Alvarez-Erviti, L. et al. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol. Dis. 42, 360–367 (2011). · DOI
  50. Vingtdeux, V. et al. Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies. J. Biol. Chem. 282, 18197–18205 (2007). · DOI
  51. Williamson, R. L. et al. Disruption of amyloid precursor protein ubiquitination selectively increases amyloid beta (Aβ) 40 levels via presenilin 2-mediated cleavage. J. Biol. Chem. 292, 19873-19889 (2017). · DOI
  52. Guix, F. X. et al. Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments. Mol. Neurodegener. 12, 25 (2017). · DOI
  53. Laulagnier, K. et al. Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem. J. 380, 161–171 (2004). · DOI
  54. Wubbolts, R. et al. Proteomic and biochemical analyses of human B cell-derived exosomes: potential implications for their function and multivesicular body formation. J. Biol. Chem. 278, 10963–10972 (2003). · DOI
  55. Clark, L. N. et al. Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed lewy body disease. PLoS ONE 10, e0125204 (2015). · DOI
  56. Meikle, P. J. et al. Effect of lysosomal storage on bis(monoacylglycero)phosphate. Biochem. J. 411, 71–78 (2008). · DOI
  57. García-Ayllón, M.-S. et al. C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease. Sci. Rep. 7, 2477 (2017). · DOI · Paper page
  58. Heneka, M. T., Golenbock, D. T. & Latz, E. Innate immunity in Alzheimer’s disease. Nat. Immunol. 16, 229–236 (2015). · DOI · Paper page
  59. Dinkins, M. B. et al. Neutral sphingomyelinase-2 deficiency ameliorates Alzheimer’ s disease pathology and improves cognition in the 5XFAD mouse. J. Neurosci. 36, 8653–8667 (2016). · DOI
  60. de Araújo, M. E. G. & Huber, L. A. Subcellular fractionation. Methods Mol. Biol. 357, 73–85 (2007).

Cited by

Sorted by citations

Metadata

Authors
Miranda, A. M., Lasiecka, Z. M., Xu, Y., Neufeld, J., Shahriar, S., Simoes, S., Chan, R. B., Oliveira, T. G., Small, S. A., & Di Paolo, G.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-01-18
Volume
9
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-017-02533-w
PMC
PMC5773483
Cited by
226
References
10
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review