Biomarkers in Neurodegenerative Diseases: Proteomics Spotlight on ALS and Parkinson’s Disease
Abstract
:1. Introduction
2. Overview of Proteomics Technological Advancement for Biomarker Discovery
3. Proteomics for Biomarker Discovery in ALS
3.1. Differential Expression of Proteins and Interactome from Post-Mortem Human Tissue as Biomarkers in ALS
3.2. Post-Translational Modifications in TDP43 from Tissue Proteomics Studies in ALS
3.3. Plasma and Serum as Sources for Proteomic Biomarkers in ALS
3.4. Cerebrospinal Fluid (CSF) Proteomic Biomarker Identification
3.5. Exosomes Proteomics in Biomarker Identification
4. Proteomics for Biomarker Discovery in PD
4.1. Differential Expression of Proteins from Post-Mortem Human Tissue as Biomarkers in PD
4.2. Post-Translational Modifications in Key Proteins from Tissue Proteomics Studies in PD
4.3. Plasma and Serum as Sources for Proteomic Biomarkers in PD
4.4. Cerebrospinal Fluid (CSF) as a Source for Proteomic Biomarkers in PD
4.5. Exosomes Proteomics in Biomarker Identification
5. Clinical Trials Using Proteomics for Biomarker Discovery in ALS and PD
6. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Method | Advantages | Disadvantages |
---|---|---|
Sample Preparation Methods | ||
Filter-aided sample preparation (FASP) | Unbiased filter-based approach which removes detergents | Molecular weight cutoffs and can be challenging for aggregated proteins |
Single-pot solid-phase-enhanced sample preparation (SP3) | Bead-based approach with low sample loss Unbiased robust recovery and can be automated using magnetic beads | Beads have a limited capacity and should not be overloaded to cause inconsistencies |
In-StageTip (iST) | Peptide can be fractionated on the tip to gain depth | Tips must be compatible with solubilization reagents used |
SarkoSpin | Can isolate insoluble pathological protein aggregated | Utilize detergents that require sample clean up prior to mass spectrometry |
Depletion | Gain depth | Low throughput, induce variability |
Immunoenrichment | Gain depth | Low throughput, induce variability |
Offline fractionation | Gain depth | Low throughput |
Mass Spectrometry Quantitation Strategies | ||
Isobaric TMT tags | Relative quantitation in MS2/MS3 dimension with multiplexing to save time | Require (SPS) MS3 for accurate quantitation to overcome challenges with ratio compression |
Label-free DIA | Relative quantitation by area under the peak, enabling the acquisition of complete data in large cohorts | Requires expertise in MS method design for window strategy and data interpretation |
MRM/PRM-targeted quantitation | Absolute quantitation with standard curves and the ability to monitor disease progression with time | Limited in the number of targets that can be analyzed |
Advances in Instrumentation and Technology | ||
BOXCAR data-independent acquisition | Improves data completeness | Requires good method design |
Real-time search RTS-SPS-MS3 | Improves quantitation | Special feature in an instrument |
High-field asymmetric ion mobility spectrometry FAIMS | Improves sensitivity and selectivity | In front end and not true ion mobility to separate isomers |
Modified LC- Evosep | Improves throughput and robustness | Has defined methods and is not customizable |
Automation | Improves reproducibility | Tedious to implement changes in workflows |
Trapped ion mobility TIMS | PTM and isoform identification | Needs expertise to achieve good separation |
Parallel acquisition serial fragmentation PASEF | Improves scan speed and sensitivity | Needs optimization based on gradient |
Multiplexed immunoassay O-link | Improves dynamic range based on antibody specificity | Limited in the panel of targets based on the availability of antibodies |
Aptamer-based assay | Improves dynamic range based on aptamer specificity | Limited in the panel of targets based on the availability of aptamers |
Disease | Marker | Quantitation | Tissue | Summary | Reference |
---|---|---|---|---|---|
Tissue-based proteomic markers in ALS | |||||
ALS | TDP43 | PRM absolute quantitation | Prefrontal/motor cortex and spinal cord | An increase in C: N-terminal TDP43 peptide ratio > 1.5, new truncation site-specific trend observed in ALS-TDP | [51,55] |
ALS (sporadic) | Calmodulin | Label-free | Spinal cord | Downregulated in ALS | [51] |
ALS (sporadic) | ATP5D | Label-free | Spinal cord | Downregulated in ALS | [51] |
ALS | UCHL1 | Label-free and MRM | Spinal cord | Upregulated in ALS and correlated with CSF | [52] |
ALS | MAP2 | Label-free and MRM | Spinal cord | Upregulated in ALS and correlated with CSF | [52] |
ALS | GPNMB | Label-free and MRM | Spinal cord | Upregulated in ALS and correlated with CSF | [52] |
Plasma/Serum proteomics biomarkers in ALS | |||||
ALS | Gelsolin | LFQ and MRM | Plasma | Differentially expressed in ALS | [56,57,58] |
ALS | Clusterin | MRM | Plasma | Downregulated in ALS | [57,58] |
ALS | CD5L | MRM | Plasma | Differentially expressed in ALS | [57,58] |
ALS | Ficolin 3 | MRM | Plasma | Upregulated in ALS | [57,58] |
CSF proteomic biomarkers in ALS | |||||
ALS | α-1-antichymotrypsin | LFQ | CSF | In CSF, 118 proteins were significantly altered in ALS compared to controls | [56] |
ALS | Amyloid beta A4 protein | LFQ | CSF | In CSF, 118 proteins were significantly altered in ALS compared to controls | [56] |
ALS | Gelsolin | LFQ | CSF | In CSF, 118 proteins were significantly altered in ALS compared to controls | [56] |
ALS | Chitinase-3-like protein 1 (CHI3L1) | LFQ | CSF | Upregulated | [59] |
ALS | Chitinase-3-like protein 2 (CHI3L2) | LFQ, TMT | CSF | Upregulated in mutated C9orf72 symptomatic ALS compared to asymptomatic controls with C9orf72 mutations | [59,60] |
ALS | Chitotriosidase-1 (CHIT-1) | LFQ, TMT | CSF | Upregulated in mutated C9orf72 symptomatic ALS compared to asymptomatic controls with C9orf72 mutations | [59,60] |
ALS | Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) | LFQ, TMT, MRM | CSF | Upregulated in mutated C9orf72 symptomatic ALS compared to asymptomatic controls with C9orf72 mutations | [52,59,60] |
ALS | MAP2 | MRM | CSF | Upregulated | [52] |
ALS | CAPG | MRM | CSF | Upregulated | [52] |
ALS | GPNMB | MRM | CSF | Upregulated | [52] |
ALS | CRYAB | TMT | CSF | Upregulated in mutated C9orf72 symptomatic ALS compared to asymptomatic controls with C9orf72 mutations | [60] |
ALS | PFN1 | TMT | CSF | Upregulated in mutated C9orf72 symptomatic ALS compared to asymptomatic controls with C9orf72 mutations | [60] |
ALS | TFRC | TMT | CSF | Upregulated in mutated C9orf72 symptomatic ALS compared to asymptomatic controls with C9orf72 mutations | [60] |
ALS | TREM2 | TMT | CSF | Upregulated in C9orf72 variant-associated symptomatic ALS compared to asymptomatic controls with C9orf72 variants | [60] |
ALS | TXNDC17 | TMT | CSF | Upregulated in mutated C9orf72 variant-associated symptomatic ALS compared to asymptomatic controls with C9orf72 variants | [60] |
ALS | NEFM | TMT | CSF | Upregulated in mutated C9orf72 symptomatic ALS compared to asymptomatic controls with C9orf72 mutations | [60] |
Exosomal biomarkers in ALS | |||||
ALS | Gelsolin | LFQ | CSF exosomes | Upregulated in C9orf mutated ALS cases | [61] |
ALS | Clusterin | LFQ | CSF exosomes | Upregulated | [61] |
ALS | UBA1 | LFQ | CSF exosomes | Upregulated in C9orf mutated ALS cases | [61] |
ALS | NIR | LFQ | CSF exosomes | Upregulated in sporadic ALS | [62] |
ALS | TDP43 | LFQ | Plasma exosomes | Levels correlated with longitudinal progression | [63] |
Disease | Marker | Quantitation | Tissue | Summary | Reference |
---|---|---|---|---|---|
Tissue-based proteomic markers in PD | |||||
PD | Mitochondrial dysfunction, oxidative stress, cytoskeleton impairment-related proteins | TMT | Substantia nigra | Significant changes in expression levels of 204 nigral proteins in human PD samples | [85] |
PD | RGS6 | LFQ | Substantia nigra (Lewy body pathology) | Changes in proteins related to (1) Arp2/3 complex-mediated actin nucleation; (2) synaptic function; (3) poly(A) RNA binding; (4) basement membrane and endothelium; and (5) hydrogen peroxide metabolic processes | [86] |
PD | GANAB | LFQ | Substantia nigra (Lewy body pathology) | Changes in proteins related to (1) Arp2/3 complex-mediated actin nucleation; (2) synaptic function; (3) poly(A) RNA binding; (4) basement membrane and endothelium; and (5) hydrogen peroxide metabolic processes | [86] |
PD | CD59 | LFQ | Substantia nigra (Lewy body pathology) | Changes in proteins related to (1) Arp2/3 complex-mediated actin nucleation; (2) synaptic function; (3) poly(A) RNA binding; (4) basement membrane and endothelium; and (5) hydrogen peroxide metabolic processes | [86] |
Plasma/serum proteomic biomarkers in PD | |||||
PD | Apolipoprotein A1 | iTRAQ | Plasma/serum | Downregulated in PD | [87,88] |
PD | Apolipoprotein A-IV | LFQ | Plasma/serum | Downregulated in PD | [87,88] |
PD | Apolipoprotein B | LFQ | Plasma | Downregulated in PD | [89] |
PD | Apolipoprotein CI | LFQ | Plasma | Downregulated in PD | [89] |
PD | Apolipoprotein CIII | LFQ | Plasma | Downregulated in PD | [89] |
PD | Apolipoprotein C4 | LFQ | Plasma | Downregulated in PD | [89] |
PD | Apolipoprotein C4 | LFQ | Plasma | Downregulated in PD | [89] |
PD | Apolipoprotein M | LFQ | Plasma | Downregulated in PD | [89] |
PD | Inter-alpha-trypsin inhibitor heavy | LFQ | Plasma/serum | Downregulated in PD | [87] |
PD | Complement C4A | LFQ | Plasma/serum | Downregulated in PD | [87] |
PD | Complement C4B | iTRAQ | Plasma/serum | Downregulated in PD | [87,88] |
PD | Complement C3 | LFQ | Plasma/serum | Downregulated in PD | [87] |
PD | Haptoglobin | LFQ | Plasma | Downregulated in PD | [89] |
PD | Clusterin | LFQ | Plasma/serum | Upregulated in PD | [87] |
PD | Transthyretin | LFQ | Plasma/serum | Upregulated in PD | [87] |
PD | Zinc α-2 glycoprotein | LFQ | Plasma/serum | Upregulated in PD | [87] |
PD | Vitamin D binding protein | LFQ | Plasma/serum | Upregulated in PD | [87] |
PD | Afamin | LFQ | Plasma/serum | Upregulated in PD | [87] |
CSF proteomic biomarkers in PD | |||||
PD | α-synuclein peptide (81–96) | MRM | CSF | α-Synuclein peptide altered in PD | [90] |
PD | α-synuclein pS129 | MRM | CSF | α-Synuclein pS129 correlates with disease severity | [91] |
PD | Granins | DIA | CSF | Granins are downregulated in PD | [92] |
Exosomal biomarkers in PD | |||||
PD | α-synuclein | LFQ | Serum neuronal(L1CAM+) exosomes | Upregulated in prodromal and clinical PD compared to controls and other neurodegenerative diseases | [93] |
PD | Clusterin | LFQ | Serum neuronal (L1CAM+) exosomes, plasma exosomes | Upregulated in FTD but not PD, served as a combined marker with α-synuclein and is downregulated in PD in plasma exosomes | [93,94] |
PD | α-synuclein | SRM | Plasma neuronal (L1CAM+) exosomes | α-synuclein is upregulated in PD | [95,96] |
PD | Complement C1r | LFQ | Plasma exosomes | Downregulated in PD | [94] |
PD | Apolipoprotein A1 | LFQ | Plasma exosomes | Downregulated in PD | [94] |
Disease | Clinical Trial | Summary | Reference |
---|---|---|---|
ALS | NCT01948102 | An observational study for the identification of prognostic and diagnostic markers in skin and adipose samples using proteomics to measure changes in abundance and/or post-translational modifications of proteins in the trial | [6] |
PD | NCT00315250 | An interventional study with the aim of developing imaging, clinical, and biochemical biomarkers for PD uses proteomics in combination with metabolomics and gene expression to categorize Parkinson’s syndrome vs. non-Parkinson’s syndrome | [7] |
PD | NCT02263235 | A study in Alzheimer’s, PD, and other neurological disorders without cognitive decline uses targeted quantitative proteomics by MRM in CSF, blood, urine, and saliva for diagnostic purposes after administering stable isotope-labelled leucine for the diagnosis of neurological disorders | [4] |
PD | NCT02524405 | An investigational study in Alzheimer’s and PD (called the brain–eye amyloid memory study (BEAM)), MRI, and amyloid PET were used for primary and secondary outcomes, genetic analysis for ApoE4 status, and proteomics and lipidomics analyses | [2] |
PD | NCT02387281 | An observational study in PD studying freezing of gait (FOG) proteomics on CSF is used in combination with analysis of catecholamines along with MRI and other cognitive tests to assess types of FOG and if there is a connection with cognitive differences and gait patterns presented in PD | [3] |
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Raghunathan, R.; Turajane, K.; Wong, L.C. Biomarkers in Neurodegenerative Diseases: Proteomics Spotlight on ALS and Parkinson’s Disease. Int. J. Mol. Sci. 2022, 23, 9299. https://doi.org/10.3390/ijms23169299
Raghunathan R, Turajane K, Wong LC. Biomarkers in Neurodegenerative Diseases: Proteomics Spotlight on ALS and Parkinson’s Disease. International Journal of Molecular Sciences. 2022; 23(16):9299. https://doi.org/10.3390/ijms23169299
Chicago/Turabian StyleRaghunathan, Rekha, Kathleen Turajane, and Li Chin Wong. 2022. "Biomarkers in Neurodegenerative Diseases: Proteomics Spotlight on ALS and Parkinson’s Disease" International Journal of Molecular Sciences 23, no. 16: 9299. https://doi.org/10.3390/ijms23169299