Deciphering Protein Secretion from the Brain to Cerebrospinal Fluid for Biomarker Discovery.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 101128775 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1535-3907 (Electronic) Linking ISSN: 15353893 NLM ISO Abbreviation: J Proteome Res Subsets: MEDLINE

Original Publication: Washington, D.C. : American Chemical Society, c2002-

Proteome* ; Biomedical Research*; Humans ; Brain ; Protein Transport ; Biological Transport ; Cerebrospinal Fluid Proteins

Cerebrospinal fluid (CSF) is an essential matrix for the discovery of neurological disease biomarkers. However, the high dynamic range of protein concentrations in CSF hinders the detection of the least abundant protein biomarkers by untargeted mass spectrometry. It is thus beneficial to gain a deeper understanding of the secretion processes within the brain. Here, we aim to explore if and how the secretion of brain proteins to the CSF can be predicted. By combining a curated CSF proteome and the brain elevated proteome of the Human Protein Atlas, brain proteins were classified as CSF or non-CSF secreted. A machine learning model was trained on a range of sequence-based features to differentiate between CSF and non-CSF groups and effectively predict the brain origin of proteins. The classification model achieves an area under the curve of 0.89 if using high confidence CSF proteins. The most important prediction features include the subcellular localization, signal peptides, and transmembrane regions. The classifier generalized well to the larger brain detected proteome and is able to correctly predict novel CSF proteins identified by affinity proteomics. In addition to elucidating the underlying mechanisms of protein secretion, the trained classification model can support biomarker candidate selection.

Lancet Neurol. 2018 Aug;17(8):721-730. (PMID: 30033062)
J Proteome Res. 2020 Jan 3;19(1):401-408. (PMID: 31773964)
Curr Opin Neurol. 2021 Apr 1;34(2):266-274. (PMID: 33470669)
PLoS One. 2018 Nov 29;13(11):e0206478. (PMID: 30496192)
Bioinformatics. 2009 Feb 15;25(4):555-6. (PMID: 19129209)
Mol Cell Proteomics. 2014 Nov;13(11):3152-63. (PMID: 25038066)
Nat Med. 2021 Jun;27(6):954-963. (PMID: 34083813)
Nat Rev Mol Cell Biol. 2020 Dec;21(12):729-749. (PMID: 33087899)
Expert Rev Proteomics. 2022 Feb;19(2):131-151. (PMID: 35466824)
Protein Eng. 1990 Dec;4(2):155-61. (PMID: 2075190)
Data Brief. 2015 Feb 20;3:103-7. (PMID: 26217727)
Mol Syst Biol. 2020 Jun;16(6):e9356. (PMID: 32485097)
Science. 2015 Jan 23;347(6220):1260419. (PMID: 25613900)
J Proteomics. 2011 Apr 1;74(4):371-88. (PMID: 21111852)
Acta Neuropathol. 2018 Dec;136(6):821-853. (PMID: 30488277)
Protein Sci. 2022 Jan;31(1):8-22. (PMID: 34717010)
Sci Adv. 2020 Oct 21;6(43):. (PMID: 33087358)
Bioinformatics. 2009 Jun 1;25(11):1422-3. (PMID: 19304878)
Proteomics Clin Appl. 2019 Jul;13(4):e1800105. (PMID: 30578620)
Cell Mol Life Sci. 2011 Mar;68(6):1011-20. (PMID: 21104290)
Nucleic Acids Res. 2022 Jan 7;50(D1):D1541-D1552. (PMID: 34791421)
PLoS Comput Biol. 2022 Aug 11;18(8):e1010357. (PMID: 35951526)
Proteomics. 2015 Sep;15(18):3163-8. (PMID: 25656970)
J Proteome Res. 2018 Dec 7;17(12):4315-4319. (PMID: 30106588)
PLoS One. 2010 Jun 11;5(6):e10980. (PMID: 20552007)
Protein J. 2019 Jun;38(3):200-216. (PMID: 31119599)
Mol Psychiatry. 2021 Jan;26(1):296-308. (PMID: 32251378)
Nat Biotechnol. 2022 Jul;40(7):1023-1025. (PMID: 34980915)
Sci Rep. 2018 Jan 22;8(1):1362. (PMID: 29358745)
Nucleic Acids Res. 2011 Aug;39(15):e102. (PMID: 21646338)
Mol Neurobiol. 2018 Oct;55(10):7789-7801. (PMID: 29460270)
Pac Symp Biocomput. 2002;:310-22. (PMID: 11928486)
Nucleic Acids Res. 2013 Jan;41(Database issue):D344-7. (PMID: 23161676)
Clin Chem. 2012 Mar;58(3):528-30. (PMID: 22194635)
Alzheimers Dement. 2016 Feb;12(2):154-163. (PMID: 26368321)
Bioinformatics. 2015 May 1;31(9):1411-9. (PMID: 25568279)
Biomark Res. 2022 Nov 15;10(1):83. (PMID: 36380380)
Bioinformatics. 2021 Dec 22;38(1):228-235. (PMID: 34398224)
J Proteome Res. 2023 Apr 7;22(4):1181-1192. (PMID: 36963412)
Annu Rev Biochem. 1990;59:237-52. (PMID: 2197976)
J Proteome Res. 2018 Dec 7;17(12):4113-4126. (PMID: 30124047)
EMBO J. 1999 Apr 1;18(7):1723-9. (PMID: 10202136)
Mol Cell Proteomics. 2021;20:100155. (PMID: 34597790)
Neurochem Res. 2012 Apr;37(4):819-25. (PMID: 22219127)
J Mol Biol. 2001 Jan 19;305(3):567-80. (PMID: 11152613)
Proteins. 2019 Jun;87(6):520-527. (PMID: 30785653)
Mol Cell Proteomics. 2021;20:100157. (PMID: 34597789)
Chromosoma. 2016 Jun;125(3):497-521. (PMID: 26464018)
J Bioinform Comput Biol. 2020 Jun;18(3):2050017. (PMID: 32576054)
J Extracell Biol. 2024 Jan 23;3(1):e120. (PMID: 38938677)
Alzheimers Res Ther. 2018 Mar 15;10(1):30. (PMID: 29544527)
CNS Neurol Disord Drug Targets. 2013 May 1;12(3):392-404. (PMID: 23469854)
J Proteome Res. 2023 Aug 4;22(8):2570-2576. (PMID: 37458416)
Protein Sci. 2005 Apr;14(4):1091-103. (PMID: 15772310)
J Proteome Res. 2022 Sep 2;21(9):2071-2074. (PMID: 36004690)
Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W362-5. (PMID: 16845026)
Data Brief. 2020 May 16;31:105704. (PMID: 32478154)
Nat Aging. 2022 Nov;2(11):1040-1053. (PMID: 37118088)
Curr Opin Struct Biol. 2001 Feb;11(1):39-46. (PMID: 11179890)
J Proteome Res. 2018 Oct 5;17(10):3418-3430. (PMID: 30207155)
Science. 2020 Mar 6;367(6482):. (PMID: 32139519)
J Proteome Res. 2021 Jan 1;20(1):751-762. (PMID: 33253581)
Bioinformatics. 2017 Nov 01;33(21):3387-3395. (PMID: 29036616)

Keywords: brain proteome; cerebrospinal fluid; fluid biomarker; machine learning; protein secretion

0 (Proteome)
0 (Cerebrospinal Fluid Proteins)

Date Created: 20230822 Date Completed: 20230906 Latest Revision: 20240924

20240924

PMC10476268

10.1021/acs.jproteome.3c00366

37606934