Dataset Information

?-Synuclein Heterocomplexes with ?-Amyloid Are Increased in Red Blood Cells of Parkinson's Disease Patients and Correlate with Disease Severity.

ABSTRACT: Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily ?-synuclein (?-syn), ?-amyloid1-42 (A?1-42) and tau, in both brain and peripheral tissues. In addition to oligomers, the role of the interactions of ?-syn with A? or tau has gradually emerged. Nevertheless, despite intensive research, NDs have no accepted peripheral markers for biochemical diagnosis. In this respect, Red Blood Cells (RBCs) are emerging as a valid peripheral model for the study of aging-related pathologies. Herein, a small cohort (N = 28) of patients affected by Parkinson's disease (PD) and age-matched controls were enrolled to detect the content of ?-syn (total and oligomeric), A?1-42 and tau (total and phosphorylated) in RBCs. Moreover, the presence of ?-syn association with tau and A?1-42 was explored by co-immunoprecipitation/western blotting in the same cells, and quantitatively confirmed by immunoenzymatic assays. For the first time, PD patients were demonstrated to exhibit ?-syn heterocomplexes with A?1-42 and tau in peripheral tissues; interestingly, ?-syn-A?1-42 concentrations were increased in PD subjects with respect to healthy controls (HC), and directly correlated with disease severity and motor deficits. Moreover, total-?-syn levels were decreased in PD subjects and inversely related to their motor deficits. Finally, an increase of oligomeric-?-syn and phosphorylated-tau was observed in RBCs of the enrolled patients. The combination of three parameters (total-?-syn, phosphorylated-tau and ?-syn-A?1-42 concentrations) provided the best fitting predictive index for discriminating PD patients from controls. Nevertheless further investigations should be required, overall, these data suggest ?-syn hetero-aggregates in RBCs as a putative tool for the diagnosis of PD.

SUBMITTER: Daniele S

PROVIDER: S-EPMC5827358 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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α-Synuclein Heterocomplexes with β-Amyloid Are Increased in Red Blood Cells of Parkinson's Disease Patients and Correlate with Disease Severity.

Daniele Simona S Frosini Daniela D Pietrobono Deborah D Petrozzi Lucia L Lo Gerfo Annalisa A Baldacci Filippo F Fusi Jonathan J Giacomelli Chiara C Siciliano Gabriele G Trincavelli Maria Letizia ML Franzoni Ferdinando F Ceravolo Roberto R Martini Claudia C Bonuccelli Ubaldo U

Frontiers in molecular neuroscience 20180222

Neurodegenerative disorders (NDs) are characterized by abnormal accumulation/misfolding of specific proteins, primarily α-synuclein (α-syn), β-amyloid<sub>1-42</sub> (Aβ<sub>1-42</sub>) and tau, in both brain and peripheral tissues. In addition to oligomers, the role of the interactions of α-syn with Aβ or tau has gradually emerged. Nevertheless, despite intensive research, NDs have no accepted peripheral markers for biochemical diagnosis. In this respect, Red Blood Cells (RBCs) are emerging as ...[more]

PMID: 29520218

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Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.

Dataset Information

?-Synuclein Heterocomplexes with ?-Amyloid Are Increased in Red Blood Cells of Parkinson's Disease Patients and Correlate with Disease Severity.

Publications

α-Synuclein Heterocomplexes with β-Amyloid Are Increased in Red Blood Cells of Parkinson's Disease Patients and Correlate with Disease Severity.

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