Discovery of Biomarkers for Amyotrophic Lateral Sclerosis from Human Cerebrospinal Fluid Using Mass-Spectrometry-Based Proteomics
Abstract
:1. Introduction
2. Methods
2.1. Collection of CSF Samples
2.2. Sample Preparation and Trypsin Digestion for Discovery Experiments
2.3. LC-MS/MS Analysis for the Discovery of Biomarker Candidates
2.4. Database Searches for Peptide and Protein Identification
2.5. Preparation of CSF Samples for the PRM Experiments
2.6. LC-MS/MS Analysis for Validation Experiments Using the PRM Method
2.7. Experimental Design and Statistical Rationale
2.8. Disclosure of Previously Published Data
3. Results
3.1. Quantitative Proteome Analysis of CSF Samples
3.2. Selection of Candidate Biomarkers for ALS
3.3. Detectability of Candidate Biomarker Proteins in Targeted PRM Analysis
3.4. Response Curve Test of Candidate Biomarker Proteins in PRM Analysis
3.5. Targeted Quantification of Candidate ALS Biomarker Peptides in CSF from ALS and HC Individuals
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Subject ID | Sample Type | Group | Gender | Race | Age | Application of the Samples in This Study |
---|---|---|---|---|---|---|
ALS01 | CSF | ALSFRS 40 | Male | White | 62 | Discovery and Validation |
ALS02 | CSF | ALSFRS 36 | Female | White | 68 | Discovery and Validation |
ALS03 | CSF | ALSFRS 44 | Male | White | 54 | Discovery and Validation |
ALS04 | CSF | ALSFRS 33 | Female | White | 55 | Discovery and Validation |
ALS05 | CSF | ALSFRS 37 | Female | White | 44 | Discovery and Validation |
ALS06 | CSF | ALSFRS 42 | Female | White | 51 | Discovery and Validation |
ALS07 | CSF | ALSFRS 42 | Male | White | 64 | Discovery and Validation |
ALS08 | CSF | ALSFRS 33 | Female | White | 52 | Discovery and Validation |
ALS09 | CSF | ALSFRS 35 | Male | White | 68 | Discovery and Validation |
ALS10 | CSF | ALSFRS 34 | Male | White | 55 | Discovery and Validation |
ALS11 | CSF | ALSFRS 34 | Male | White | 61 | Discovery and Validation |
ALS12 | CSF | ALSFRS 35 | Male | White | 79 | Discovery and Validation |
ALS13 | CSF | ALSFRS 42 | Male | White | 63 | Discovery and Validation |
ALS14 | CSF | ALSFRS 40 | Male | White | 59 | Discovery and Validation |
ALS15 | CSF | ALSFRS 44 | Female | White | 66 | Discovery and Validation |
ALS16 | CSF | ALSFRS 43 | Male | White | 73 | Discovery and Validation |
ALS17 | CSF | ALSFRS 41 | Male | White | 55 | Discovery and Validation |
ALS18 | CSF | ALSFRS 48 | Male | White | 65 | Discovery and Validation |
ALS19 | CSF | ALSFRS 46 | Male | White | 40 | Discovery and Validation |
ALS20 | CSF | ALSFRS 34 | Female | White | 53 | Discovery and Validation |
ALS21 | CSF | No score | Male | White | 64 | Validation |
ALS22 | CSF | ALSFRS 32 | Male | White | 58 | Validation |
ALS23 | CSF | ALSFRS 42 | Male | White | 45 | Validation |
ALS24 | CSF | ALSFRS 40 | Female | White | 41 | Validation |
ALS25 | CSF | ALSFRS 47 | Male | White | 44 | Validation |
ALS26 | CSF | ALSFRS 41 | Male | White | 51 | Validation |
ALS27 | CSF | ALSFRS 40 | Male | White | 68 | Validation |
ALS28 | CSF | ALSFRS 27 | Female | White | 44 | Validation |
ALS29 | CSF | ALSFRS 48 | Male | White | 57 | Validation |
ALS30 | CSF | ALSFRS 15 | Female | White | 63 | Validation |
HC01 | CSF | Healthy Control | Male | White | 38 | Discovery and Validation |
HC02 | CSF | Healthy Control | Male | White | 58 | Discovery and Validation |
HC03 | CSF | Healthy Control | Female | White | 23 | Discovery and Validation |
HC04 | CSF | Healthy Control | Female | White | 58 | Discovery and Validation |
HC05 | CSF | Healthy Control | Female | Asian | 43 | Discovery and Validation |
HC06 | CSF | Healthy Control | Male | White | 35 | Discovery and Validation |
HC07 | CSF | Healthy Control | Male | White | 57 | Discovery and Validation |
HC08 | CSF | Healthy Control | Female | White | 46 | Discovery and Validation |
HC09 | CSF | Healthy Control | Male | White | 76 | Discovery and Validation |
HC10 | CSF | Healthy Control | Female | White | 44 | Discovery and Validation |
HC11 | CSF | Healthy Control | Female | White | 47 | Discovery and Validation |
HC12 | CSF | Healthy Control | Male | White | 70 | Discovery and Validation |
HC13 | CSF | Healthy Control | Female | White | 62 | Discovery and Validation |
HC14 | CSF | Healthy Control | Male | White | 74 | Discovery and Validation |
HC15 | CSF | Healthy Control | Male | White | 66 | Discovery and Validation |
HC16 | CSF | Healthy Control | Male | White | 72 | Discovery and Validation |
HC17 | CSF | Healthy Control | Female | White | 62 | Discovery and Validation |
HC18 | CSF | Healthy Control | Female | White | 66 | Discovery and Validation |
HC19 | CSF | Healthy Control | Male | White | 69 | Discovery and Validation |
HC20 | CSF | Healthy Control | Female | White | 55 | Discovery and Validation |
HC21 | CSF | Healthy Control | Female | White | 61 | Validation |
HC22 | CSF | Healthy Control | Male | White | 66 | Validation |
HC23 | CSF | Healthy Control | Male | White | 67 | Validation |
HC24 | CSF | Healthy Control | Female | White | 64 | Validation |
HC25 | CSF | Healthy Control | Female | ND | 59 | Validation |
HC26 | CSF | Healthy Control | Male | White | 65 | Validation |
HC27 | CSF | Healthy Control | Male | White | 66 | Validation |
HC28 | CSF | Healthy Control | Female | White | 58 | Validation |
HC29 | CSF | Healthy Control | Male | White | 54 | Validation |
HC30 | CSF | Healthy Control | Female | White | 59 | Validation |
HC31 | CSF | Healthy Control | Female | ND | 60 | Validation |
Name | Gene Symbol | p Value | q-Value | Log2 (ALS/HC) | Detectability by PRM | q-Value |
---|---|---|---|---|---|---|
Chitinase-3-like protein 2 | CHI3L2 | 2.01 × 10−8 | 0 | 2.527697 | <0.05 | |
Chitotriosidase-1 | CHIT1 | 1.88 × 10−5 | 0 | 3.99428 | Detectable | |
Neurofilament light polypeptide | NEFL | 1.47 × 10−7 | 0 | 1.722488 | ||
Neurofilament medium polypeptide | NEFM | 6.97 × 10−11 | 0 | 3.784436 | ||
Neurofilament heavy polypeptide | NEFH | 5.91 × 10−5 | 0.001333 | 2.779995 | ||
Alpha-1-antichymotrypsin | SERPINA3 | 6.94 × 10−6 | 0.008571 | 1.077944 | Detectable | |
Ubiquitin carboxyl-terminal hydrolase isozyme L1 | UCHL1 | 1.48 × 10−5 | 0.015 | 1.012955 | Detectable | |
Transmembrane glycoprotein NMB | GPNMB | 8.06 × 10−5 | 0.0244 | 1.069444 | Detectable | |
Multiple epidermal-growth-factor-like domains protein 8 | MEGF8 | 4.36 × 10−6 | 0.026182 | −0.72796 | Detectable | |
Aspartate aminotransferase, mitochondrial | GOT2 | 0.00032 | 0.026222 | 1.511867 | ||
Centromere protein F | CENPF | 0.001221 | 0.028 | 2.205369 | ||
Neuronal pentraxin-2 | NPTX2 | 0.00016 | 0.028667 | −1.13379 | Detectable | |
Calcium/calmodulin-dependent protein kinase type II subunit alpha | CAMK2A | 0.000116 | 0.033143 | −0.95518 | Detectable | |
Apolipoprotein B-100 | APOB | 0.002532 | 0.041053 | 2.13572 | Detectable | |
Amyloid-beta A4 protein | APP | 6.85 × 10−5 | 0.042444 | −0.75982 | Detectable | |
Neural cell adhesion molecule L1 | L1CAM | 7.59 × 10−5 | 0.043 | −0.74116 | Detectable | |
Chitinase-3-like protein 1 | CHI3L1 | 0.000583 | 0.044 | 1.137858 | Detectable | |
Platelet factor 4 | PF4 | 0.002747 | 0.044533 | 2.573066 | ||
Lysozyme C | LYZ | 0.000368 | 0.0465 | 1.015916 | ||
Calsyntenin-1 | CLSTN1 | 0.000146 | 0.051429 | −0.75724 | Detectable | <0.1 |
Contactin-associated protein-like 2 | CNTNAP2 | 0.000225 | 0.052182 | −0.79877 | Detectable | |
Macrophage-capping protein | CAPG | 0.00037 | 0.056522 | 0.840849 | ||
Triosephosphate isomerase | TPI1 | 2.87 × 10−5 | 0.05712 | −0.59761 | Detectable | |
Microfibril-associated glycoprotein 4 | MFAP4 | 0.00012 | 0.058429 | −0.66703 | Detectable | |
Endoplasmic reticulum aminopeptidase 2 | ERAP2 | 0.001754 | 0.058897 | 1.147899 | Detectable | |
Gamma-crystallin D | CRYGD | 0.007001 | 0.058963 | −2.86543 | ||
Syndecan binding protein (Syntenin), isoform CRA_a | SDCBP | 0.000461 | 0.059 | 0.846597 | ||
Follistatin-related protein 4 | FSTL4 | 0.000542 | 0.059333 | −0.82485 | Detectable | |
Transport and Golgi organization protein 1 homolog | MIA3 | 4.14 × 10−7 | 0.061231 | −0.45853 | ||
Neurocan core protein | NCAN | 0.000476 | 0.070545 | −0.73593 | Detectable | |
Platelet basic protein | PPBP | 0.006893 | 0.072625 | 2.127046 | Detectable | |
Leukotriene A-4 hydrolase | LTA4H | 8.72 × 10−5 | 0.073677 | 0.593814 | Detectable | |
Chondroitin sulfate proteoglycan 5 | CSPG5 | 0.001286 | 0.083412 | −0.84017 | Detectable | |
Band 4.1-like protein 3 | EPB41L3 | 0.004408 | 0.092686 | 1.101059 | ||
Immunoglobulin heavy variable 2-5 | IGHV2-5 | 0.010187 | 0.096522 | 1.802516 | ||
Plectin | PLEC | 0.00037 | 0.096681 | 0.586559 | ||
Myosin light chain kinase, smooth muscle | MYLK | 0.000406 | 0.09688 | 0.572703 | ||
Calsyntenin-3 | CLSTN3 | 8.53 × 10−5 | 0.097255 | −0.49128 | Detectable | |
Serine/threonine-protein phosphatase 2A activator | PTPA | 0.000505 | 0.0978 | 0.637236 | ||
UMP-CMP kinase | CMPK1 | 0.002623 | 0.097956 | 0.843523 | ||
Neuronal pentraxin-1 | NPTX1 | 0.002511 | 0.098222 | −0.79414 | Detectable | |
Alpha-1-antitrypsin | SERPINA1 | 0.002667 | 0.098449 | 0.842153 | Detectable | |
Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 | LINGO1 | 0.000955 | 0.098462 | −0.65034 | Detectable | |
Immunoglobulin lambda variable 3-19 | IGLV3-19 | 0.006846 | 0.098537 | 1.408966 | Detectable | |
Immunoglobulin lambda variable 3-27 | IGLV3-27 | 0.003614 | 0.098566 | 0.886375 | ||
Alpha-2,8-sialyltransferase 8E | ST8SIA5 | 0.000228 | 0.098974 | −0.5754 | Detectable | |
Butyrophilin subfamily 3 member A2 | BTN3A2 | 0.005124 | 0.099 | 1.036734 | ||
Reticulon-4 receptor-like 2 | RTN4RL2 | 0.00064 | 0.099111 | −0.67662 | Detectable | |
Protein kinase C-binding protein NELL2 | NELL2 | 0.001377 | 0.099135 | −0.78332 | Detectable | |
Immunoglobulin J chain | JCHAIN | 0.010018 | 0.099167 | 1.661328 | Detectable | |
Multiple epidermal-growth-factor-like domains protein 9 | MEGF9 | 0.000603 | 0.099263 | −0.66189 | ||
Glutathione S-transferase Mu 1 | GSTM1 | 0.008847 | 0.09981 | 1.620058 | ||
Neurofascin | NFASC | 0.00052 | 0.099907 | −0.62704 | Detectable |
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Share and Cite
Oh, S.; Jang, Y.; Na, C.H. Discovery of Biomarkers for Amyotrophic Lateral Sclerosis from Human Cerebrospinal Fluid Using Mass-Spectrometry-Based Proteomics. Biomedicines 2023, 11, 1250. https://doi.org/10.3390/biomedicines11051250
Oh S, Jang Y, Na CH. Discovery of Biomarkers for Amyotrophic Lateral Sclerosis from Human Cerebrospinal Fluid Using Mass-Spectrometry-Based Proteomics. Biomedicines. 2023; 11(5):1250. https://doi.org/10.3390/biomedicines11051250
Chicago/Turabian StyleOh, Sungtaek, Yura Jang, and Chan Hyun Na. 2023. "Discovery of Biomarkers for Amyotrophic Lateral Sclerosis from Human Cerebrospinal Fluid Using Mass-Spectrometry-Based Proteomics" Biomedicines 11, no. 5: 1250. https://doi.org/10.3390/biomedicines11051250