Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport
| Autor: | Beat Kunz, Mitsuo Tagaya, Alexander Ludwig, Tu-My Diep, Martin Steuble, Peter Sonderegger, Philipp Schätzle |
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| Přispěvatelé: | University of Zurich, Sonderegger, Peter |
| Rok vydání: | 2012 |
| Předmět: |
QH301-705.5
Endosome Science ADAM10 1100 General Agricultural and Biological Sciences Biology Endocytosis Anterograde axonal transport General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine 1300 General Biochemistry Genetics and Molecular Biology mental disorders 10019 Department of Biochemistry β-secretase Calsyntenin Biology (General) Growth cone 030304 developmental biology 0303 health sciences BACE1 Amyloid β Alzheimer's disease Cell biology Vesicular transport protein Ectodomain Calsyntenin-1 570 Life sciences biology APP α-secretase General Agricultural and Biological Sciences 030217 neurology & neurosurgery Research Article |
| Zdroj: | Biol Open Biology Open Biology Open, Vol 1, Iss 8, Pp 761-774 (2012) |
| Popis: | Summary Endocytosis of amyloid-β precursor protein (APP) is thought to represent the major source of substrate for the production of the amyloidogenic Aβ peptide by the β-secretase BACE1. The irreversible nature of proteolytic cleavage implies the existence of an efficient replenishment route for APP from its sites of synthesis to the cell surface. We recently found that APP exits the trans-Golgi network in intimate association with calsyntenin-1, a transmembrane cargo-docking protein for Kinesin-1-mediated vesicular transport. Here we characterized the function of calsyntenin-1 in neuronal APP transport using selective immunoisolation of intracellular trafficking organelles, immunocytochemistry, live-imaging, and RNAi. We found that APP is co-transported with calsyntenin-1 along axons to early endosomes in the central region of growth cones in carriers that exclude the α-secretase ADAM10. Intriguingly, calsyntenin-1/APP organelles contained BACE1, suggesting premature cleavage of APP along its anterograde path. However, we found that APP contained in calsyntenin-1/APP organelles was stable. We further analyzed vesicular trafficking of APP in cultured hippocampal neurons, in which calsyntenin-1 was reduced by RNAi. We found a markedly increased co-localization of APP and ADAM10 in axons and growth cones, along with increased proteolytic processing of APP and Aβ secretion in these neurons. This suggested that the reduced capacity for calsyntenin-1-dependent APP transport resulted in mis-sorting of APP into additional axonal carriers and, therefore, the premature encounter of unprotected APP with its ectodomain proteases. In combination, our results characterize calsyntenin-1/APP organelles as carriers for sheltered anterograde axonal transport of APP. |
| Databáze: | OpenAIRE |
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