Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration
Abstract
Because accumulation of alpha-synuclein (alphaS) in the brain is a hallmark of Parkinson disease (PD) and related disorders, we examined its occurrence in human cerebrospinal fluid (CSF). Following affinity enrichment and trypsin digestion of CSF collected from a neurologically healthy donor, we identified several alphaS-derived peptides by mass spectrometry. The concentration of alphaS amounted to <0.001% of the CSF proteome. We then built, validated and optimized a sandwich-type, enzyme-linked immunoadsorbent assay (ELISA) to measure total alphaS levels in unconcentrated CSF. In a cross-sectional study of 100 living donors, we examined cell-free CSF samples from subjects clinically diagnosed with advanced PD, dementia with Lewy bodies (DLB), Alzheimer disease (AD), and a group of non-neurodegenerative disease controls (NCO). In these four groups the CSF alphaS concentrations ranged from 0.8 to 16.2 pg/microl. Mean CSF alphaS values were lower in donors with a primary synucleinopathy (PD, DLB: n=57) than in the other two groups (AD, NCO: n=35; p=0.025). By contrast, living Creutzfeldt-Jakob disease patients showed markedly elevated CSF alphaS levels (n=8; mean, 300 pg/microl; p<0.001). Our results unequivocally confirm the presence of alphaS in adult human CSF. In a first feasibility study employing a novel ELISA, we found relatively low CSF alphaS concentrations in subjects with parkinsonism linked to synucleinopathy, PD and DLB. In definite prion disease cases, we recorded a marked rise in total CSF alphaS resulting from rapid cell death. Our results will likely aid future biomarker explorations in neurodegenerative conditions and facilitate target validation studies.
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Numerous studies have documented unaltered or slightly increased cerebrospinal fluid αSyn levels in patients with mild cognitive impairment and Alzheimer's disease.
“numerous studies have documented unaltered or slightly increased CSF αSyn levels in patients with MCI and AD [27, 80–82, 86, 90, 91, 93, 94].”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [82]
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- Authors
- Mollenhauer, B., Cullen, V., Kahn, I., Krastins, B., Outeiro, T. F., Pepivani, I., Ng, J., Schulz-Schaeffer, W., Kretzschmar, H. A., McLean, P. J., Trenkwalder, C., Sarracino, D. A., VonSattel, J.-P., Locascio, J. J., El-Agnaf, O. M. A., & Schlossmacher, M. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Ottawa (CA)
- Ludwig-Maximilians-Universität München (DE)
- Paracelsus Elena Klinik Kassel (DE)
- Columbia University (US)
- Corresponding author
- Schlossmacher, Michael G.
- ORCID
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 213
- Issue
- 2
- Pages
- 315-325
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2003260773
- Cited by
- 382
- References
- 68
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 8 · 2023: 9 · 2022: 22 · 2021: 16 · 2020: 25 · 2019: 19 · 2018: 16 · 2017: 17 · 2016: 20 · 2015: 25 · 2014: 32 · 2013: 26 · 2012: 30
- FWCI
- 19.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (P50NS038375, 5P50-NS038375)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- alpha-synuclein, cerebrospinal fluid, Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, Creutzfeldt-Jakob disease, synucleinopathies, cell-free biomarkers, ELISA quantification, neurodegeneration, prion disease, cell death
- MeSH terms
- Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Animals, Cells, Cultured, Cross-Sectional Studies, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Nerve Degeneration, Biomarkers, Mice, Rats, alpha-Synuclein
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