α-synuclein−lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients

Paslawski, Wojciech; Zarȩba-Pasławska, Justyna; Zhang, Xiaoqun; Hölzl, Katharina; Wadensten, Henrik; Shariatgorji, Mohammadreza; Bateman, Randall J.; Hansson, Oskar; Forsgren, Lars; Andrén, Per E.; Svenningsson, Per

doi:10.1073/pnas.1821409116

Cited by 39 publications

(40 citation statements)

References 65 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5A). This phenomenon was previously observed [27,57,58] and, although not being fully understood, it could be produced by the interaction between α-syn and CSF protein constituents [42,59]. From Fig.…”

Section: Variables Influencing α-Synuclein Seed Amplification Assayssupporting

confidence: 63%

Seed amplification assays for diagnosing synucleinopathies: the issue of influencing factors

Bellomo

Paciotti

Gatticchi

et al. 2021

Front. Biosci. (Landmark Ed)

View full text Add to dashboard Cite

Background: The prion-like misfolding and aggregation of α-synuclein (α-syn) is involved in the pathophysiology of Parkinson’s disease and other synucleinopathies. Seed amplification assays (SAAs) are biophysical tools that take advantage on the peculiar properties of prion proteins by amplifying small amounts of aggregates in biological fluids at the expense of recombinant monomeric protein added in solution. SAAs have emerged as the most promising tools for the diagnosis of synucleinopathies in vivo. However, the diagnostic outcome of SAAs depends on the aggregation kinetics of α-syn, which in turn is influenced by several experimental variables. Methods: In our work, we analysed the impact on SAAs of some of the most critical experimental factors by considering models that describe the aggregation kinetics of α-syn. Results: We started our analysis by making simulations to understand which kinetic models could explain the aggregation kinetics of α-syn during incubation/shaking cycles. Subsequently, under shaking/incubation cycles similar to the ones commonly used in SAAs, we tested the influence of some analytical variables such as monomer concentration, presence/absence of glass beads, pH, addition of human cerebrospinal fluid, and use of detergents on α-syn aggregation. Conclusions: Our investigation highlighted how optimization and standardization of experimental procedures for α-syn SAAs is of utmost relevance for the ultimate goal of applying these assays in clinical routine. Although these aspects have been evaluated with specific SAA protocols, most of the experimental variables considered influenced very general aggregation mechanisms of α-syn, thus making most of the results obtained from our analyses extendable to other protocols.

show abstract

Section: Variables Influencing α-Synuclein Seed Amplification Assayssupporting

confidence: 63%

Seed amplification assays for diagnosing synucleinopathies: the issue of influencing factors

Bellomo

Paciotti

Gatticchi

et al. 2021

Front. Biosci. (Landmark Ed)

View full text Add to dashboard Cite

show abstract

“…The SDS-PAGE was performed as previously described ( 20 ). The sample was mixed in a 3:1 ratio with denaturing loading buffer (106 mM Tris-HCl, 141 mM Tris, 2% lithium dodecyl sulfate (LDS), 10% glycerol, 6% β-mercaptoethanol, 0.51 mM EDTA, 0.22 mM SERVA Blue G-250, 0.175 mM Phenol Red, pH 8.5) and boiled at 95°C for 5 min.…”

Section: Methodsmentioning

confidence: 99%

Tau Isoform-Driven CBD Pathology Transmission in Oligodendrocytes in Humanized Tau Mice

et al. 2021

Self Cite

View full text Add to dashboard Cite

The aggregation of abnormally phosphorylated tau protein in neurons and glia is a neuropathological hallmark of several neurodegenerative disorders, collectively known as tauopathies. They are further subclassified based on the preferential pathological aggregation of three carboxyl-terminal repeat domains (3R) and/or 4R tau. Corticobasal degeneration (CBD) is a rare neurodegenerative disorder classified as a 4R tauopathy. In the present study, we extend analysis of CBD-tau cell-type specific pathology transmission with 3R and 4R tau isoform distinguishable changes. We use a humanized tau (hTau) mouse line, which overexpress all six human tau isoforms in a murine tau knockout background and perform intrastriatal inoculation of control and CBD-tau enriched human brain homogenate. We show that CBD-tau causes hyperphosphorylation of tau at Ser202 predominantly in oligodendrocytes. Next, we demonstrate the spread of tau pathology from striatum to the overlaying corpus callosum and further to the contralateral side. Finally, we demonstrate that the almost exclusive oligodendrocyte-based transmission of hyperphosphorylated tau is reflected in the endogenous 4R tau isoform expression and corresponds to subclassification of CBD as a 4R tauopathy. Additionally, we identify functional changes in oligodendrocytes reflected by myelin basic protein abnormalities upon CBD-tau inoculation. These changes are not observed in murine tau knockout mice lacking both human and murine tau. Our study presents not only in vivo tau isoform–driven region- and cell-specific tau pathology, but also underlines that tau pathology seeding and transmission might be oligodendrocyte-based. These results, which need to be extended to more cases, give new insights into why tauopathies might vary greatly in both histopathological and neuroanatomical patterns.

show abstract

“…Interestingly, recent studies have suggested that PD may be not only a proteinopathy but also a lipidopathy [22]. Around 40% of CSF alfa-Syn is found in lipoprotein particles [23]. Finally, as in most chronic diseases, inflammation contributes to the pathogenesis of PD.…”

Section: Disease Biology In Pdmentioning

confidence: 99%

Genetically Targeted Clinical Trials in Parkinson’s Disease: Learning from the Successes Made in Oncology

Sjögren

Huttunen

Svenningsson

et al. 2021

Genes

Self Cite

View full text Add to dashboard Cite

Clinical trials in neurodegenerative disorders have been associated with high rate of failures, while in oncology, the implementation of precision medicine and focus on genetically defined subtypes of disease and targets for drug development have seen an unprecedented success. With more than 20 genes associated with Parkinson’s disease (PD), most of which are highly penetrant and often cause early onset or atypical signs and symptoms, and an increasing understanding of the associated pathophysiology culminating in dopaminergic neurodegeneration, applying the technologies and designs into the field of neurodegeneration seems a logical step. This review describes some of the methods used in oncology clinical trials and some attempts in Parkinson’s disease and the potential of further implementing genetics, biomarkers and smart clinical trial designs in this disease area.

show abstract

α-synuclein−lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients

Cited by 39 publications

References 65 publications

Seed amplification assays for diagnosing synucleinopathies: the issue of influencing factors

Seed amplification assays for diagnosing synucleinopathies: the issue of influencing factors

Tau Isoform-Driven CBD Pathology Transmission in Oligodendrocytes in Humanized Tau Mice

Genetically Targeted Clinical Trials in Parkinson’s Disease: Learning from the Successes Made in Oncology

Contact Info

Product

Resources

About