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Cerebrospinal fluid lipoproteins inhibit α-synuclein aggregation by interacting with oligomeric species in seed amplification assays.

Authors :
Bellomo, Giovanni
Paciotti, Silvia
Concha-Marambio, Luis
Rizzo, Domenico
Wojdaƚa, Anna Lidia
Chiasserini, Davide
Gatticchi, Leonardo
Cerofolini, Linda
Giuntini, Stefano
De Luca, Chiara Maria Giulia
Ma, Yihua
Farris, Carly M.
Pieraccini, Giuseppe
Bologna, Sara
Filidei, Marta
Ravera, Enrico
Lelli, Moreno
Moda, Fabio
Fragai, Marco
Parnetti, Lucilla
Source :
Molecular Neurodegeneration. 4/1/2023, Vol. 18 Issue 1, p1-24. 24p.
Publication Year :
2023

Abstract

Background: Aggregation of α-synuclein (α-syn) is a prominent feature of Parkinson's disease (PD) and other synucleinopathies. Currently, α-syn seed amplification assays (SAAs) using cerebrospinal fluid (CSF) represent the most promising diagnostic tools for synucleinopathies. However, CSF itself contains several compounds that can modulate the aggregation of α-syn in a patient-dependent manner, potentially undermining unoptimized α-syn SAAs and preventing seed quantification. Methods: In this study, we characterized the inhibitory effect of CSF milieu on detection of α-syn aggregates by means of CSF fractionation, mass spectrometry, immunoassays, transmission electron microscopy, solution nuclear magnetic resonance spectroscopy, a highly accurate and standardized diagnostic SAA, and different in vitro aggregation conditions to evaluate spontaneous aggregation of α-syn. Results: We found the high-molecular weight fraction of CSF (> 100,000 Da) to be highly inhibitory on α-syn aggregation and identified lipoproteins to be the main drivers of this effect. Direct interaction between lipoproteins and monomeric α-syn was not detected by solution nuclear magnetic resonance spectroscopy, on the other hand we observed lipoprotein-α-syn complexes by transmission electron microscopy. These observations are compatible with hypothesizing an interaction between lipoproteins and oligomeric/proto-fibrillary α-syn intermediates. We observed significantly slower amplification of α-syn seeds in PD CSF when lipoproteins were added to the reaction mix of diagnostic SAA. Additionally, we observed a decreased inhibition capacity of CSF on α-syn aggregation after immunodepleting ApoA1 and ApoE. Finally, we observed that CSF ApoA1 and ApoE levels significantly correlated with SAA kinetic parameters in n = 31 SAA-negative control CSF samples spiked with preformed α-syn aggregates. Conclusions: Our results describe a novel interaction between lipoproteins and α-syn aggregates that inhibits the formation of α-syn fibrils and could have relevant implications. Indeed, the donor-specific inhibition of CSF on α-syn aggregation explains the lack of quantitative results from analysis of SAA-derived kinetic parameters to date. Furthermore, our data show that lipoproteins are the main inhibitory components of CSF, suggesting that lipoprotein concentration measurements could be incorporated into data analysis models to eliminate the confounding effects of CSF milieu on α-syn quantification efforts. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
17501326
Volume :
18
Issue :
1
Database :
Academic Search Index
Journal :
Molecular Neurodegeneration
Publication Type :
Academic Journal
Accession number :
162869509
Full Text :
https://doi.org/10.1186/s13024-023-00613-8