Balklava, Zita, Niehage, Christian, Currinn, Heather, Mellor, Laura, Guscott, Benjamin, Poulin, Gino, Hoflack, Bernard and Wassmer, Thomas (2015). The amyloid precursor protein controls PIKfyve function. PLoS ONE, 10 (6),
Abstract
While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease.
Publication DOI: | https://doi.org/10.1371/journal.pone.0130485 |
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Divisions: | College of Health & Life Sciences College of Health & Life Sciences > School of Biosciences College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine |
Additional Information: | © 2015 Balklava et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Alzheimer Research UK ARUK-PHD-12/13; BBSRC BB/K014862/1 (TW and ZB); Royal Society (ZB); Deutsche Forschungsgemeinschaft TRR 83/1-2010, HO 2584/1-1, HO 2584/2-1, HO 2584/6-1, HO 2584/8-1, HO 2584/9-1 (BH); BBSRC (BB/J014834/1). LM is funded by a BBSRC DTP (BB/J014478/1). |
Uncontrolled Keywords: | General Agricultural and Biological Sciences,General Biochemistry,Genetics and Molecular Biology,General Medicine |
Publication ISSN: | 1932-6203 |
Last Modified: | 06 Aug 2024 07:24 |
Date Deposited: | 02 Jul 2015 13:15 |
Full Text Link: |
http://journals ... al.pone.0130485 |
Related URLs: |
http://www.scop ... tnerID=8YFLogxK
(Scopus URL) |
PURE Output Type: | Article |
Published Date: | 2015-06-30 |
Authors: |
Balklava, Zita
(![]() Niehage, Christian Currinn, Heather Mellor, Laura Guscott, Benjamin Poulin, Gino Hoflack, Bernard Wassmer, Thomas |