Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport
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 AP...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2012-06-01
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| Series: | Biology Open |
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| Online Access: | http://bio.biologists.org/content/1/8/761 |
| _version_ | 1818656780454985728 |
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| author | Martin Steuble Tu-My Diep Philipp Schätzle Alexander Ludwig Mitsuo Tagaya Beat Kunz Peter Sonderegger |
| author_facet | Martin Steuble Tu-My Diep Philipp Schätzle Alexander Ludwig Mitsuo Tagaya Beat Kunz Peter Sonderegger |
| author_sort | Martin Steuble |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T03:31:01Z |
| format | Article |
| id | doaj.art-0d6f6491a8aa47e5a7e382d68d207390 |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-17T03:31:01Z |
| publishDate | 2012-06-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-0d6f6491a8aa47e5a7e382d68d2073902022-12-21T22:05:16ZengThe Company of BiologistsBiology Open2046-63902012-06-011876177410.1242/bio.2012157820121578Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transportMartin Steuble0Tu-My Diep1Philipp Schätzle2Alexander Ludwig3Mitsuo Tagaya4Beat Kunz5Peter Sonderegger6 Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland 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.http://bio.biologists.org/content/1/8/761APPAnterograde axonal transportCalsyntenin-1Alzheimer's diseaseAmyloid βα-secretaseβ-secretaseADAM10BACE1 |
| spellingShingle | Martin Steuble Tu-My Diep Philipp Schätzle Alexander Ludwig Mitsuo Tagaya Beat Kunz Peter Sonderegger Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport Biology Open APP Anterograde axonal transport Calsyntenin-1 Alzheimer's disease Amyloid β α-secretase β-secretase ADAM10 BACE1 |
| title | Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport |
| title_full | Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport |
| title_fullStr | Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport |
| title_full_unstemmed | Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport |
| title_short | Calsyntenin-1 shelters APP from proteolytic processing during anterograde axonal transport |
| title_sort | calsyntenin 1 shelters app from proteolytic processing during anterograde axonal transport |
| topic | APP Anterograde axonal transport Calsyntenin-1 Alzheimer's disease Amyloid β α-secretase β-secretase ADAM10 BACE1 |
| url | http://bio.biologists.org/content/1/8/761 |
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