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The structural differences between patient-derived ?-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies.

ABSTRACT: Synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of ?-synuclein (?SYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar ?SYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different ?SYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct ?SYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of ?SYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of ?SYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human ?SYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified ?SYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of ?SYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, ?SYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains.

SUBMITTER: Van der Perren A

PROVIDER: S-EPMC7244622 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies.

Van der Perren Anke A Gelders Géraldine G Fenyi Alexis A Bousset Luc L Brito Filipa F Peelaerts Wouter W Van den Haute Chris C Gentleman Steve S Melki Ronald R Baekelandt Veerle V

Acta neuropathologica 20200430 6

Synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible ...[more]

PMID: 32356200

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Project description:Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer's disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.

Project description:IntroductionParkinson's disease (PD) and Dementia with Lewy bodies (DLB) show heterogeneous brain atrophy patterns which group-average analyses fail to capture. Neuroanatomical normative modelling overcomes this by comparing individuals to a large reference cohort. Patient-specific atrophy patterns are measured objectively and summarised to index overall neurodegeneration (the 'total outlier count'). We aimed to quantify patterns of neurodegenerative dissimilarity in participants with PD and DLB and evaluate the potential clinical relevance of total outlier count by testing its association with key clinical measures in PD and DLB.Materials and methodsWe included 108 participants with PD and 61 with DLB. PD participants were subclassified into high and low visual performers as this has previously been shown to stratify those at increased dementia risk. We generated z-scores from T1w-MRI scans for each participant relative to normative regional cortical thickness and subcortical volumes, modelled in a reference cohort (n = 58,836). Outliers (z < -1.96) were aggregated across 169 brain regions per participant. To measure dissimilarity, individuals' Hamming distance scores were calculated. We also examined total outlier counts between high versus low visual performance in PD; and PD versus DLB; and tested associations between these and cognition.ResultsThere was significantly greater inter-individual dissimilarity in brain-outlier patterns in PD poor compared to high visual performers (W = 522.5; p < 0.01) and in DLB compared to PD (W = 5649; p < 0.01). PD poor visual performers had significantly greater total outlier counts compared to high (β = -4.73 (SE = 1.30); t = -3.64; p < 0.01) whereas a conventional group-level GLM failed to identify differences. Higher total outlier counts were associated with poorer MoCA (β = -0.55 (SE = 0.27), t = -2.04, p = 0.05) and composite cognitive scores (β = -2.01 (SE = 0.79); t = -2.54; p = 0.02) in DLB, and visuoperception (β = -0.67 (SE = 0.19); t = -3.59; p < 0.01), in PD.ConclusionsNeuroanatomical normative modelling shows promise as a clinically informative technique in PD and DLB, where patterns of atrophy are variable.

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Project description:Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of ?-synuclein protein (?-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of ?-syn, and phosphorylated and phosphorylated oligomeric forms of ?-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of ?-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric ?-syn, and phosphorylated ?-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric ?-syn did differ significantly (p<0.001) amongst the different diagnostic groups. Although all 4 measures of ?-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p<0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of ?-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other ?-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of ?-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric ?-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.

Dataset Information

The structural differences between patient-derived ?-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies.

Publications

The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies.

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