Cerebrospinal α‐Synuclein Oligomers Reflect Disease Motor Severity in <scp>DeNoPa</scp> Longitudinal Cohort

Majbour, Nour K.; Abdi, Ilham Y.; Dakna, Mohammed; Wicke, Tamara; Lang, Elisabeth; Moussa, Houda Yasmine Ali; Thomas, Mercy; Trenkwalder, Claudia; Safieh‐Garabedian, Bared; Tokuda, Takahiko; Mollenhauer, Brit; El‐Agnaf, Omar M. A.

doi:10.1002/mds.28611

Cited by 24 publications

(27 citation statements)

References 37 publications

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“…A number of studies measured α-syn levels from the blood and CSF. This was carried out also aiming at specific isoforms of α-syn (monomer vs. oligomers Miki et al 2018 ; Majbour et al 2021 ; soluble vs. insoluble Prigione et al 2010 ), which best characterize PD. The present study confirms a significant increase of α-syn levels, here measured using ultrastructural stoichiometry evidence.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies in the last two decades probed the amount of α-syn in the blood, CSF and other fluids including saliva as a feasible marker in PD (Vivacqua et al 2016 ; Wang et al 2015 ). These studies became more and more elaborated in detecting specific protein conformation and providing a significant correlation between PD and specific isoform of α-syn in various fluids (Majbour et al 2021 ; Wang et al 2015 ; Graham et al 2019 ). Again, since α-syn accumulation is related to an impairment of its metabolism which mainly takes place via the autophagy machinery (Petroi et al 2012 ; Limanaqi et al 2020 ; Langston and Cookson 2020 ), autophagy-related proteins were measured in PD patients (e.g., Wu et al 2011 ; Miki et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

“…The present study was carried out with the aim to improve the power for a potential peripheral marker of PD. In fact, despite assay of specific α-syn isoform in the CSF provides significant differences between PD and controls which may be correlated with some items of the disease course (Majbour et al 2021 ), a clear-cut difference between values measured in single PD patients compared with single controls is not present; the same applies for specific autophagy proteins. This means that some overlapping in data distribution exists.…”

Section: Introductionmentioning

confidence: 99%

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An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease

et al. 2021

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Peripheral markers in Parkinson’s disease (PD) represent a hot issue to provide early diagnosis and assess disease progression. The gold standard marker of PD should feature the same reliability as the pathogenic alteration, which produces the disease itself. PD is foremost a movement disorder produced by a loss of nigrostriatal dopamine innervation, in which striatal dopamine terminals are always markedly reduced in PD patients to an extent, which never overlaps with controls. Similarly, a reliable marker of PD should possess such a non-overlapping feature when compared with controls. In the present study, we provide a novel pathological hallmark, the autophagosome, which in each PD patient was always suppressed compared with each control subject. Autophagosomes were counted as microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive vacuoles at ultrastructural morphometry within peripheral (blood) blood mononuclear cells (PBMC). This also provides the gold standard to assess the autophagy status. Since autophagy may play a role in the pathogenesis of PD, autophagosomes may be a disease marker, while participating in the biology of the disease. Stoichiometric measurement of α-synuclein despite significantly increased in PD patients, overlapped between PD and control patients. Although the study need to be validated in large populations, the number of autophagy vacuoles is neither related with therapy (the amount was similarly suppressed in a few de novo patients), nor the age in PD or controls.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease

et al. 2021

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“…Recently, the measurement of oligomeric α-Syn in biofluid has emerged as a promising approach to diagnose PD. Several studies have reported higher oligomeric α-Syn levels or ratio of oligomeric/total α-Syn in cerebrospinal fluid and red blood cells in PD patients than in healthy controls ( Tian et al, 2019 ; Majbour et al, 2021 ). Notably, oligomeric α-Syn were also detected in biofluids from healthy control individuals although at lower concentrations.…”

Section: Discussionmentioning

confidence: 99%

Oral Mucosa Derived α−Synuclein as a Potential Diagnostic Biomarker for Parkinson′s Disease

Zheng

Cai

et al. 2022

Front. Aging Neurosci.

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BackgroundPathological α-synuclein (α-Syn) is not only exclusive to the central nervous system (CNS) in Parkinson’s disease (PD), but also extended to biofluids and peripheral tissues including oral cavity. Both oral mucosa and nervous system are derived from ectodermal tissue, and potentially share common disease-specific characteristics. Oral mucosal exfoliative cytology is a non-invasive technique, which is an easily acceptable for patients and ordinary people. The purpose of this study was to determine the abnormal accumulation of α-Syn in oral mucosa of PD patients and to learn the diagnostic utility of oral mucosa α-Syn for PD.MethodsThe oral mucosa samples were obtained from 57 patients with PD and 51 age-matched controls by cytological brush. Immunofluorescence analysis was used to investigate the presence and subcellular localization of α-Syn, phosphorylated α-Syn at Ser129 (pS129) and oligomeric α-Syn in the oral mucosa cells of PD patients and controls. Images taken as Z-stacks were analyzed for 3D reconstruction to visualize the α-Syn intracellular localization. Then, the concentrations of α-Syn, pS129, and oligomeric α-Syn in oral mucosa samples were measured using electrochemiluminescence assays.ResultsImmunofluorescence images revealed the increased α-Syn, pS129, and oligomeric α-Syn levels in oral mucosa cells of PD patients than age-matched controls. The intracellular distributions of α-Syn species were determine by Z-stack images with 3D reconstruction, and α-Syn was detected in both the nucleus and cytoplasm. However, pS129 was mainly located in the cytoplasm, and oligomeric α-Syn was highly expressed in the nucleus and perinuclear cytoplasm. The concentrations of three α-Syn species were significantly increased in the oral mucosa cell samples of PD patients than controls (α-Syn, p = 0.001; pS129, p = 0.002; oligomeric α-Syn, p = 0.013). In PD patients, the oral mucosa α-Syn and oligomeric α-Syn levels were significantly correlated with Hoehn-Yahr scales (α-Syn, r = 0.495, p = 0.001; oligomeric α-Syn, r = 0.324, p = 0.03). The area under curve (AUC) of ROC analysis using an integrative model including α-Syn, pS129, and oligomeric α-Syn for PD diagnosis was 0.749, with 66.7% sensitivity and 72.5% specificity.ConclusionThis study for the first time demonstrated increased expressions of α-Syn, pS129, and oligomeric α-Syn in oral mucosa cells from PD patients, which serve as useful and non-invasive PD diagnostic biomarkers.

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“…Consequently, a number of drug candidates have been designed to interfere with the aggregation pathway aiming to eliminate existing oligomers or to prevent their formation 6 . Since aggregate formation reflects pathophysiological changes inside the brain, oligomers have also been proposed as promising biomarker candidates 7 – 9 . However, quantitative measurement of oligomers is technically challenging and mainly hampered by three technical issues.…”

Section: Introductionmentioning

confidence: 99%

Quantitative detection of α-Synuclein and Tau oligomers and other aggregates by digital single particle counting

Blömeke

Pils

Kraemer-Schulien

et al. 2022

npj Parkinsons Dis.

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The pathological hallmark of neurodegenerative diseases is the formation of toxic oligomers by proteins such as alpha-synuclein (aSyn) or microtubule-associated protein tau (Tau). Consequently, such oligomers are promising biomarker candidates for diagnostics as well as drug development. However, measuring oligomers and other aggregates in human biofluids is still challenging as extreme sensitivity and specificity are required. We previously developed surface-based fluorescence intensity distribution analysis (sFIDA) featuring single-particle sensitivity and absolute specificity for aggregates. In this work, we measured aSyn and Tau aggregate concentrations of 237 cerebrospinal fluid (CSF) samples from five cohorts: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and a neurologically-normal control group. aSyn aggregate concentration discriminates PD and DLB patients from normal controls (sensitivity 73%, specificity 65%, area under the receiver operating curve (AUC) 0.68). Tau aggregates were significantly elevated in PSP patients compared to all other groups (sensitivity 87%, specificity 70%, AUC 0.76). Further, we found a tight correlation between aSyn and Tau aggregate titers among all patient cohorts (Pearson coefficient of correlation r = 0.81). Our results demonstrate that aSyn and Tau aggregate concentrations measured by sFIDA differentiate neurodegenerative disease diagnostic groups. Moreover, sFIDA-based Tau aggregate measurements might be particularly useful in distinguishing PSP from other parkinsonisms. Finally, our findings suggest that sFIDA can improve pre-clinical and clinical studies by identifying those individuals that will most likely respond to compounds designed to eliminate specific oligomers or to prevent their formation.

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Cerebrospinal α‐Synuclein Oligomers Reflect Disease Motor Severity in DeNoPa Longitudinal Cohort

Cited by 24 publications

References 37 publications

An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease

An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease

Oral Mucosa Derived α−Synuclein as a Potential Diagnostic Biomarker for Parkinson′s Disease

Quantitative detection of α-Synuclein and Tau oligomers and other aggregates by digital single particle counting

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