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Label-free Quantitative Proteomics of Mouse Cerebrospinal Fluid Detects β-Site APP Cleaving Enzyme (BACE1) Protease Substrates In Vivo
Abstract
Analysis of murine cerebrospinal fluid (CSF) by quantitative mass spectrometry is challenging because of low CSF volume, low total protein concentration, and the presence of highly abundant proteins such as albumin. We demonstrate that the CSF proteome of individual mice can be analyzed in a quantitative manner to a depth of several hundred proteins in a robust and simple workflow consisting of single ultra HPLC runs on a benchtop mass spectrometer. The workflow is validated by a comparative analysis of BACE1-/- and wild-type mice using label-free quantification. The protease BACE1 cleaves the amyloid precursor protein (APP) as well as several other substrates and is a major drug target in Alzheimer's disease. We identified a total of 715 proteins with at least 2 unique peptides and quantified 522 of those proteins in CSF from BACE1-/- and wild-type mice. Several proteins, including the known BACE1 substrates APP, APLP1, CHL1 and contactin-2 showed lower abundance in the CSF of BACE1-/- mice, demonstrating that BACE1 substrate identification is possible from CSF. Additionally, ectonucleotide pyrophosphatase 5 was identified as a novel BACE1 substrate and validated in cells using immunoblots and by an in vitro BACE1 protease assay. Likewise, receptor-type tyrosine-protein phosphatase N2 and plexin domain-containing 2 were confirmed as BACE1 substrates by in vitro assays. Taken together, our study shows the deepest characterization of the mouse CSF proteome to date and the firs…
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More than 40 substrate candidates for BACE1 were identified in recent proteomic studies in murine neurons or CSF, but only a few have been validated with functional or in vitro assays, including L1, CHL1, ENPP5 and PTPRN2.
“More than 40 substrate candidates for BACE1 were identified in recent proteomic studies in murine neurons or cerebrospinal fluid (CSF), but only a few of them have been validated to date with functional or in vitro assays, including L1, CHL1, ENPP5 and PTPRN2 [12, 14–16].”
From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [14]
Recent proteomic studies have identified more than 40 membrane proteins as potential BACE1 substrates.
“Recent proteomic studies have identified more than 40 membrane proteins as potential BACE1 substrates [14–16].”
From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [14]
A previous proteomic study demonstrated that the soluble ectodomains of other BACE1 substrates, such as APLP1, PLXDC2 and CHL1, were reduced in the CSF of BACE1-deficient mice.
“A previous proteomic study demonstrated that the soluble ectodomains of other BACE1 substrates, such as APLP1, PLXDC2 and CHL1, were reduced in the CSF of BACE1-deficient mice [14].”
From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [14]
The new workflow allowed the quantification of SEZ6 and SEZ6L, which were not quantified in the previous study.
“Importantly, the new workflow allowed the quantification of SEZ6 and SEZ6L, which were not quantified in the previous study [14].”
From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [14]
With the optimized protocol, SEZ6 and SEZ6L were quantified in murine CSF, whereas they were not quantified in the previous study.
“In contrast to our previous proteomic study of CSF from BACE1 deficient mice [14], we were able to quantify SEZ6 and SEZ6L with the optimized protocol (Additional file 2: Supplementary Data: proteins BACE DKO vs WT CSF).”
From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [14]
sSEZ6 and sSEZ6L were not consistently detected and could not be quantified in murine CSF in the previous study.
“However, sSEZ6 and sSEZ6L were not consistently detected and could not be quantified in murine CSF, potentially because their levels were below the detection limit.”
From Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons (2016) · cites this paper as [14]
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Metadata
- Authors
- Dislich, B., Wohlrab, F., Bachhuber, T., Müller, S. A., Kuhn, P.-H., Hogl, S., Meyer-Luehmann, M., & Lichtenthaler, S. F.
- Venue
- Molecular & Cellular Proteomics
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 14
- Issue
- 10
- Pages
- 2550-2563
- ISSN
- 1535-9476
- Cited by
- 85
- References
- 6
- Language
- en
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