The Amyloid Precursor Protein Controls PIKfyve Function.
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...
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doaj-37a975215e6641dea43cf0d7be01a4342020-11-25T01:51:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01106e013048510.1371/journal.pone.0130485The Amyloid Precursor Protein Controls PIKfyve Function.Zita BalklavaChristian NiehageHeather CurrinnLaura MellorBenjamin GuscottGino PoulinBernard HoflackThomas WassmerWhile 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.http://europepmc.org/articles/PMC4488396?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zita Balklava Christian Niehage Heather Currinn Laura Mellor Benjamin Guscott Gino Poulin Bernard Hoflack Thomas Wassmer |
spellingShingle |
Zita Balklava Christian Niehage Heather Currinn Laura Mellor Benjamin Guscott Gino Poulin Bernard Hoflack Thomas Wassmer The Amyloid Precursor Protein Controls PIKfyve Function. PLoS ONE |
author_facet |
Zita Balklava Christian Niehage Heather Currinn Laura Mellor Benjamin Guscott Gino Poulin Bernard Hoflack Thomas Wassmer |
author_sort |
Zita Balklava |
title |
The Amyloid Precursor Protein Controls PIKfyve Function. |
title_short |
The Amyloid Precursor Protein Controls PIKfyve Function. |
title_full |
The Amyloid Precursor Protein Controls PIKfyve Function. |
title_fullStr |
The Amyloid Precursor Protein Controls PIKfyve Function. |
title_full_unstemmed |
The Amyloid Precursor Protein Controls PIKfyve Function. |
title_sort |
amyloid precursor protein controls pikfyve function. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4488396?pdf=render |
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