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Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer's and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies.

ABSTRACT: ?-Synuclein (?Syn) is a major constituent of proteinaceous aggregates in neurodegenerative diseases such as Parkinson's disease (PD) and a potential biomarker candidate for diagnosis and treatment effects. However, studies about ?Syn in cerebrospinal fluid (CSF) in diseases are inconsistent and mainly based on immunological assays. Quantitative information about ?-synuclein (?Syn) and ?-synuclein (?Syn) in CSF is not available.Here, we present an alternative method for the simultaneous quantification of ?Syn, ?Syn and ?Syn in CSF by multiple reaction monitoring (MRM) with a high sequence coverage (70%) of ?Syn to validate previous, ELISA-based results and characterize synucleins in CSF in more detail.The MRM has high sensitivity in the low pg/ml range (3-30pg/ml full-length ?Syn) using 200 ?l CSF. A high portion of CSF ?Syn is present in the N-terminally acetylated form and the concentration of unmodified peptides in the nonamyloid component region is about 40% lower than in the N-terminal region. Synuclein concentrations show a high correlation with each other in CSF (r>0.80) and in contrast to ?Syn and ?Syn, ?Syn is not affected by blood contamination. CSF ?Syn, ?Syn and ?Syn concentrations were increased in Alzheimer's and Creutzfeldt-Jakob disease but not altered in PD, PD dementia (PDD), Lewy body dementia and atypical parkinsonian syndromes. The ratio ?Syn/?Syn was increased in PDD (1.49 ± 0.38, p < 0.05) compared with PD (1.11 ± 0.26) and controls (1.15 ± 0.28). ?Syn shows a high correlation with CSF tau concentrations (r = 0.86, p < 0.0001, n = 125).In conclusion, we could not confirm previous observations of reduced ?Syn in PD and our results indicate that CSF synuclein concentrations are rather general markers of synaptic degeneration than specific for synucleinopathies. ?syn is an attractive biomarker candidate that might be used as an alternative to or in combination with tau in AD and CJD diagnosis and in combination with ?Syn it is a biomarker candidate for PDD.

SUBMITTER: Oeckl P

PROVIDER: S-EPMC5054339 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer's and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies.

Oeckl Patrick P Metzger Fabian F Nagl Magdalena M von Arnim Christine A F CA Halbgebauer Steffen S Steinacker Petra P Ludolph Albert C AC Otto Markus M

Molecular & cellular proteomics : MCP 20160809 10

α-Synuclein (αSyn) is a major constituent of proteinaceous aggregates in neurodegenerative diseases such as Parkinson's disease (PD) and a potential biomarker candidate for diagnosis and treatment effects. However, studies about αSyn in cerebrospinal fluid (CSF) in diseases are inconsistent and mainly based on immunological assays. Quantitative information about β-synuclein (βSyn) and γ-synuclein (γSyn) in CSF is not available.Here, we present an alternative method for the simultaneous quantific ...[more]

PMID: 27507836

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Project description:UNLABELLED:Fast, definitive diagnosis of Creutzfeldt-Jakob disease (CJD) is important in assessing patient care options and transmission risks. Real-time quaking-induced conversion (RT-QuIC) assays of cerebrospinal fluid (CSF) and nasal-brushing specimens are valuable in distinguishing CJD from non-CJD conditions but have required 2.5 to 5 days. Here, an improved RT-QuIC assay is described which identified positive CSF samples within 4 to 14 h with better analytical sensitivity. Moreover, analysis of 11 CJD patients demonstrated that while 7 were RT-QuIC positive using the previous conditions, 10 were positive using the new assay. In these and further analyses, a total of 46 of 48 CSF samples from sporadic CJD patients were positive, while all 39 non-CJD patients were negative, giving 95.8% diagnostic sensitivity and 100% specificity. This second-generation RT-QuIC assay markedly improved the speed and sensitivity of detecting prion seeds in CSF specimens from CJD patients. This should enhance prospects for rapid and accurate ante mortem CJD diagnosis. IMPORTANCE:A long-standing problem in dealing with various neurodegenerative protein misfolding diseases is early and accurate diagnosis. This issue is particularly important with human prion diseases, such as CJD, because prions are deadly, transmissible, and unusually resistant to decontamination. The recently developed RT-QuIC test allows for highly sensitive and specific detection of CJD in human cerebrospinal fluid and is being broadly implemented as a key diagnostic tool. However, as currently applied, RT-QuIC takes 2.5 to 5 days and misses 11 to 23% of CJD cases. Now, we have markedly improved RT-QuIC analysis of human CSF such that CJD and non-CJD patients can be discriminated in a matter of hours rather than days with enhanced sensitivity. These improvements should allow for much faster, more accurate, and practical testing for CJD. In broader terms, our study provides a prototype for tests for misfolded protein aggregates that cause many important amyloid diseases, such as Alzheimer's, Parkinson's, and tauopathies.

Dataset Information

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer's and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies.

Publications

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer's and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies.

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