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Super-resolution microscopy reveals majorly mono- and dimeric presenilin1/γ-secretase at the cell surface

Escamilla-Ayala, Abril Angélica, Sannerud, Ragna, Mondin, Magali, Poersch, Karin, Vermeire, Wendy, Paparelli, Laura, Berlage, Caroline, Koenig, Marcelle, Chavez-Gutierrez, Lucia, Ulbrich, Maximilian H, Munck, Sebastian, Mizuno, Hideaki, Annaert, Wim·2020·eLife
DOI 10.7554/elife.56679PMC PMC7340497
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Abstract

γ-Secretase is a multi-subunit enzyme whose aberrant activity is associated with Alzheimer’s disease and cancer. While its structure is atomically resolved, γ-secretase localization in the membrane in situ relies mostly on biochemical data. Here, we combined fluorescent tagging of γ-secretase subunits with super-resolution microscopy in fibroblasts. Structured illumination microscopy revealed single γ-secretase complexes with a monodisperse distribution and in a 1:1 stoichiometry of PSEN1 and nicastrin subunits. In living cells, sptPALM revealed PSEN1/γ-secretase mainly with directed motility and frequenting ‘hotspots’ or high track-density areas that are sensitive to γ-secretase inhibitors. We visualized γ-secretase association with substrates like amyloid precursor protein and N-cadherin, but not with its sheddases ADAM10 or BACE1 at the cell surface, arguing against pre-formed megadalton complexes. Nonetheless, in living cells PSEN1/γ-secretase transiently visits ADAM10 hotspots. Our results highlight the power of super-resolution microscopy for the study of γ-secretase distribution and dynamics in the membrane.

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  • Cholesterol unloading decreases Aβ formation in cell culture and on the plasma membrane.

    “and is consistent with cholesterol unloading decreasing Aβ formation in cell culture (63) and on the plasma membrane (64).”

    From Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol (2021) · cites this paper as [64]

    The Introduction discusses cholesterol associated with γ-secretase, and the Results examine γ-secretase at the plasma membrane, but neither reports that cholesterol unloading decreases Aβ formation there. Searches for cholesterol depletion and cholesterol-related Aβ production found no passage addressing that effect. The cell-culture portion is attached to a different citation. (LLM, conf=0.76)

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Metadata

Authors
Escamilla-Ayala, A. A., Sannerud, R., Mondin, M., Poersch, K., Vermeire, W., Paparelli, L., Berlage, C., Koenig, M., Chavez-Gutierrez, L., Ulbrich, M. H., Munck, S., Mizuno, H., & Annaert, W.
Affiliations
  • Laboratory for Membrane Trafficking, VIB-KU Leuven Center for Brain and Disease Research, Leuven, Belgium
  • Bordeaux Imaging Center, UMS 3420, CNRS-University of Bordeaux, US4 INSERM, Bordeaux, France
  • Faculty of Biology, University of Freiburg, Freiburg, Germany
  • Einstein Center for Neurosciences, NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • PicoQuant GmbH, Berlin, Germany
  • Department of Neurosciences, KU Leuven, Leuven, Belgium
  • Institute of Internal Medicine IV, Medical Center of the University of Freiburg, Freiburg, Germany
  • Laboratory of Biomolecular Network Dynamics, Biochemistry, Molecular and Structural Biology Section, KU Leuven, Heverlee, Belgium
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-07-07
Volume
9
ISSN
2050-084X
DOI
10.7554/elife.56679
PMC
PMC7340497
Cited by
29
References
3
Language
en
Licence
Funders
  • KU Leuven (IDO/12/020, C16/15/073)
  • Fonds Wetenschappelijk Onderzoek (S006617N, G078117N, G056017N, AKUL/08/58, AKUL/11/30, AKUL/13/39)
  • Agence Nationale de la Recherche (ANR-10-INBS-04)
  • European Molecular Biology Organization (#8358)
  • SAO-FRA (#14017)

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