Biomarkers in Neurodegenerative Diseases: Proteomics Spotlight on ALS and Parkinson’s Disease

Raghunathan, Rekha; Turajane, Kathleen; Wong, Li Chin

doi:10.3390/ijms23169299

Cited by 18 publications

(12 citation statements)

References 122 publications

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“…The identified peptides in our dataset are only partially new compared to those in previous studies 14,15 . The differences may be due to enhanced sensitivity of the utilized peptide quantification methods or the fact that the biomarker discovery method used in the majority of earlier studies is different from our holistic and nondigestive peptidomics approach.…”

Section: Discussionmentioning

confidence: 66%

Small peptide fingerprint (peptidomics) of Amyotrophic Lateral Sclerosis in CSF

Lumi,

Petri,

Siwy

et al. 2023

Preprint

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BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by abnormal protein aggregates in motor neurons. Present and earlier proteomic studies to characterize peptides in cerebrospinal fluid (CSF) associated with motoneuron pathology did not target the low molecular weight proteins and peptides. We generated the hypothesis that specific changes in CSF peptides or low molecular weight proteins are significantly changed in ALS, and that these changes may support deciphering molecular pathophysiology and even guide approaches towards therapeutic interventions.MethodsCerebrospinal fluid (CSF) from 50 ALS patients and 50 non-ALS controls was collected, centrifuged immediately after collection, aliquoted into polypropylene test tubes, frozen within 30–40 min after the puncture and stored at −80°C until use. Peptides were sequenced using capillary electrophoresis or liquid chromatography / mass spectrometry (CE-MS/MS or LC-MS/MS) analyses.FindingsIn cerebrospinal CSF from 50 patients and 50 non-ALS controls 33 peptides were found, of which 14 could be sequenced using a non-lytic single pot proteomic detection method, CE/MS. ALS deregulated peptides vs. controls included Integral membrane protein 2B, Neurosecretory protein VGF, Osteopontin, Neuroendocrine protein 7B2 (Secretogranin-V), EGF-containing fibulin-like extracellular matrix protein 1, Xylosyltransferase 1 XT-1, Chromogranin-A, Superoxide dismutase SOD-1, Secretogranin-1 (Chromogranin B), NR2F2 Nuclear Receptor Subfamily 2 Group F Member 2 and Collagen alpha-1(VII) chain.InterpretationMost striking deregulations in CSF from ALS patients were found in VGF, Osteopontin, SOD-1 and EFEMP1 peptides. No associations of disease severity, duration and region of onset with sequenced peptides were found.Declarations of InterestS. Petri received honoraria as speaker/consultant from Biogen GmbH, Roche, Novartis, Teva, Cytokinetics Inc., Desitin, Italfarmaco, Ferrer, Amylyx, and Zambon; and grants from DGM e.V, Federal Ministry of Education and Research, German Israeli Foundation for Scientific Research and Development, EU Joint Program for Neurodegenerative Disease Research. J. Beige received funding from GSK and German Federal Ministries of Research and Health.FundingThere was no funding to the presented investigationEthical ApprovalThis study was approved by the ethics committee of Hannover Medical School. Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki. Key words: ALS, CSF, proteomics, biomarker, peptidomics, peptide deregulation

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Section: Discussionmentioning

confidence: 66%

Small peptide fingerprint (peptidomics) of Amyotrophic Lateral Sclerosis in CSF

Lumi,

Petri,

Siwy

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The identified peptides in our dataset are only partially new compared to those in previous studies [ 16 , 17 ]. The differences may be due to enhanced sensitivity of the utilized peptide quantification methods or the fact that the biomarker discovery method used in the majority of earlier studies is different from our holistic and non-digestive peptidomics approach.…”

Section: Discussionmentioning

confidence: 68%

Small peptide CSF fingerprint of amyotrophic lateral sclerosis

Lumi,

Petri,

Siwy

et al. 2024

PLoS ONE

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Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by abnormal protein aggregation in the motor neurons. Present and earlier proteomic studies to characterize peptides in cerebrospinal fluid (CSF) associated with motoneuron pathology did not target low molecular weight proteins and peptides. We hypothesized that specific changes in CSF peptides or low molecular weight proteins are significantly altered in ALS, and that these changes may support deciphering molecular pathophysiology and even guide approaches towards therapeutic interventions. Methods Cerebrospinal fluid (CSF) from 50 ALS patients and 50 non-ALS controls was collected, centrifuged immediately after collection, aliquoted into polypropylene test tubes, frozen within 30–40 min after the puncture, and stored at −80°C until use. Peptides were sequenced using capillary electrophoresis or liquid chromatography/mass spectrometry (CE-MS/MS or LC-MS/MS). Findings In the CSF of 50 patients and 50 non-ALS controls 33 peptides were found, of which 14 could be sequenced using a non-lytic single-pot proteomic detection method, CE/MS. ALS deregulated peptides vs. controls included Integral membrane protein 2B, Neurosecretory protein VGF, Osteopontin, Neuroendocrine protein 7B2 (Secretogranin-V), EGF-containing fibulin-like extracellular matrix protein 1, Xylosyltransferase 1 XT-1, Chromogranin-A, Superoxide dismutase SOD-1, Secretogranin-1 (Chromogranin B), NR2F2 Nuclear Receptor Subfamily 2 Group F Member 2 and Collagen alpha-1(VII) chain. Interpretation Most striking deregulations in CSF from ALS patients were found in VGF, Osteopontin, SOD-1 and EFEMP1 peptides. No associations of disease severity, duration and region of onset with sequenced peptides were found.

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“…Towards this end, we performed discovery-based studies on pre-fractionated CSF from 20 patients with ALS and 20 HC individuals using an 11-plex TMT platform and discovered 53 candidate ALS biomarker proteins (19 candidates with q < 0.05 and 34 candidates with q < 0.1). Among the 53 candidate ALS biomarker proteins, 44 proteins are novel, and 9 proteins were identified previously as being differentially expressed in ALS, and these include neurofilament proteins (NEFL, NEFM, and NEFH), CHIT1, CHI3L1, CHI3L2, APOB, GPNMB, and UCHL1 [20,41,42]. Neurofilament proteins are intermediate filament proteins that are elevated in response to neuronal damage [25,43], while CHIT1, CHI3L1, and CHI3L2 are members of the human chitinase family that are implicated in inflammation [24].…”

Section: Discussionmentioning

confidence: 99%

Discovery of Biomarkers for Amyotrophic Lateral Sclerosis from Human Cerebrospinal Fluid Using Mass-Spectrometry-Based Proteomics

Jang

2023

Biomedicines

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, which eventually may lead to death. Critical to the mission of developing effective therapies for ALS is the discovery of biomarkers that can illuminate mechanisms of neurodegeneration and have diagnostic, prognostic, or pharmacodynamic value. Here, we merged unbiased discovery-based approaches and targeted quantitative comparative analyses to identify proteins that are altered in cerebrospinal fluid (CSF) from patients with ALS. Mass spectrometry (MS)-based proteomic approaches employing tandem mass tag (TMT) quantification methods from 40 CSF samples comprising 20 patients with ALS and 20 healthy control (HC) individuals identified 53 proteins that are differential between the two groups after CSF fractionation. Notably, these proteins included both previously identified ones, validating our approach, and novel ones that have the potential for expanding biomarker repertoire. The identified proteins were subsequently examined using parallel reaction monitoring (PRM) MS methods on 61 unfractionated CSF samples comprising 30 patients with ALS and 31 HC individuals. Fifteen proteins (APOB, APP, CAMK2A, CHI3L1, CHIT1, CLSTN3, ERAP2, FSTL4, GPNMB, JCHAIN, L1CAM, NPTX2, SERPINA1, SERPINA3, and UCHL1) showed significant differences between ALS and the control. Taken together, this study identified multiple novel proteins that are altered in ALS, providing the foundation for developing new biomarkers for ALS.

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Biomarkers in Neurodegenerative Diseases: Proteomics Spotlight on ALS and Parkinson’s Disease

Cited by 18 publications

References 122 publications

Small peptide fingerprint (peptidomics) of Amyotrophic Lateral Sclerosis in CSF

Small peptide fingerprint (peptidomics) of Amyotrophic Lateral Sclerosis in CSF

Small peptide CSF fingerprint of amyotrophic lateral sclerosis

Discovery of Biomarkers for Amyotrophic Lateral Sclerosis from Human Cerebrospinal Fluid Using Mass-Spectrometry-Based Proteomics

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