The amyloid precursor protein of Alzheimer’s disease clusters at the organelle/microtubule interface on organelles that bind microtubules in an ATP dependent manner
Stevenson, James W.
Conaty, Eliza A.
Walsh, Rylie B.
Poidomani, Paul J.
Samoriski, Colin M.
Scollins, Brianne J.
DeGiorgis, Joseph A.
MetadataShow full item record
The amyloid precursor protein (APP) is a causal agent in the pathogenesis of Alzheimer’s disease and is a transmembrane protein that associates with membrane-limited organelles. APP has been shown to co-purify through immunoprecipitation with a kinesin light chain suggesting that APP may act as a trailer hitch linking kinesin to its intercellular cargo, however this hypothesis has been challenged. Previously, we identified an mRNA transcript that encodes a squid homolog of human APP770. The human and squid isoforms share 60% sequence identity and 76% sequence similarity within the cytoplasmic domain and share 15 of the final 19 amino acids at the C-terminus establishing this highly conserved domain as a functionally import segment of the APP molecule. Here, we study the distribution of squid APP in extruded axoplasm as well as in a well-characterized reconstituted organelle/microtubule preparation from the squid giant axon in which organelles bind microtubules and move towards the microtubule plus-ends. We find that APP associates with microtubules by confocal microscopy and co-purifies with KI-washed axoplasmic organelles by sucrose density gradient fractionation. By electron microscopy, APP clusters at a single focal point on the surfaces of organelles and localizes to the organelle/microtubule interface. In addition, the association of APP-organelles with microtubules is an ATP dependent process suggesting that the APP-organelles contain a microtubule-based motor protein. Although a direct kinesin/APP association remains controversial, the distribution of APP at the organelle/microtubule interface strongly suggests that APP-organelles have an orientation and that APP like the Alzheimer’s protein tau has a microtubule-based function.
© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS One 11 (2016): e0147808, doi:10.1371/journal.pone.0147808.
The following license files are associated with this item:
Showing items related by title, author, creator and subject.
Graham, David M.; Messerli, Mark A.; Pethig, Ronald (Informa Healthcare USA, 2012-01)The selection, isolation, and accurate positioning of single cells in three dimensions are increasingly desirable in many areas of cell biology and tissue engineering. We describe the application of a simple and low cost ...
Rediscovery of the nucleolinus, a dynamic RNA-rich organelle associated with the nucleolus, spindle, and centrosomes Alliegro, Mary Anne; Henry, Jonathan J.; Alliegro, Mark C. (2010-06)The nucleolinus is an RNA-rich compartment, closely apposed to or embedded within the nucleolus. Discovered over 150 years ago, fewer than two dozen articles have been published on the nucleolinus, probably because complex ...
Insights into transcriptional changes that accompany organelle sequestration from the stolen nucleus of Mesodinium rubrum Lasek-Nesselquist, Erica; Wisecaver, Jennifer H.; Hackett, Jeremiah D.; Johnson, Matthew D. (BioMed Central, 2015-10-16)Organelle retention is a form of mixotrophy that allows organisms to reap metabolic benefits similar to those of photoautotrophs through capture of algal prey and sequestration of their plastids. Mesodinium rubrum is an ...