Pigoni, M;
Wanngren, J;
Kuhn, P-H;
Munro, KM;
Gunnersen, JM;
Takeshima, H;
Feederle, R;
... Lichtenthaler, SF; + view all
(2016)
Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons.
Molecular Neurodegeneration
, 11
(ARTN 67)
10.1186/s13024-016-0134-z.
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Abstract
Background: The protease BACE1 (beta-site APP cleaving enzyme) is a major drug target in Alzheimer’s disease. However, BACE1 therapeutic inhibition may cause unwanted adverse effects due to its additional functions in the nervous system, such as in myelination and neuronal connectivity. Additionally, recent proteomic studies investigating BACE1 inhibition in cell lines and cultured murine neurons identified a wider range of neuronal membrane proteins as potential BACE1 substrates, including seizure protein 6 (SEZ6) and its homolog SEZ6L. Methods and results: We generated antibodies against SEZ6 and SEZ6L and validated these proteins as BACE1 substrates in vitro and in vivo. Levels of the soluble, BACE1-cleaved ectodomain of both proteins (sSEZ6, sSEZ6L) were strongly reduced upon BACE1 inhibition in primary neurons and also in vivo in brains of BACE1-deficient mice. BACE1 inhibition increased neuronal surface levels of SEZ6 and SEZ6L as shown by cell surface biotinylation, demonstrating that BACE1 controls surface expression of both proteins. Moreover, mass spectrometric analysis revealed that the BACE1 cleavage site in SEZ6 is located in close proximity to the membrane, similar to the corresponding cleavage site in SEZ6L. Finally, an improved method was developed for the proteomic analysis of murine cerebrospinal fluid (CSF) and was applied to CSF from BACE-deficient mice. Hereby, SEZ6 and SEZ6L were validated as BACE1 substrates in vivo by strongly reduced levels in the CSF of BACE1-deficient mice. Conclusions: This study demonstrates that SEZ6 and SEZ6L are physiological BACE1 substrates in the murine brain and suggests that sSEZ6 and sSEZ6L levels in CSF are suitable markers to monitor BACE1 inhibition in mice.
| Type: | Article |
|---|---|
| Title: | Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13024-016-0134-z |
| Publisher version: | http://dx.doi.org/10.1186/s13024-016-0134-z |
| Language: | English |
| Additional information: | © The Author(s). 2016 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Alzheimer's disease, BACE1, BACE2, Secretase, Neuroproteomics, Biomarker, SEZ6, SEZ6L, AMYLOID PRECURSOR PROTEIN, REGULATED INTRAMEMBRANE PROTEOLYSIS, BETA-SECRETASE BACE1, ALZHEIMERS-DISEASE, CELL-ADHESION, PROTEOMIC ANALYSIS, MASS-SPECTROMETRY, ASPARTYL PROTEASE, MEMORY DEFICITS, IN-VIVO |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1526431 |
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