Heterogeneity in α-synuclein fibril activity correlates to disease phenotypes in Lewy body dementia

Abstract

α-Synuclein aggregation underlies pathological changes in Lewy body dementia. Recent studies highlight structural variabilities associated with α-synuclein aggregates in patient populations.Here, we develop a quantitative real-time quaking-induced conversion (qRT-QuIC) assay to measure permissive α-synuclein fibril-templating activity in tissues and cerebrospinal fluid (CSF).The assay is anchored through reference panels of stabilized ultra-short fibril particles. In humanized α-synuclein transgenic mice, qRT-QuIC identifies differential levels of fibril activity across the brain months before the deposition of phosphorylated α-synuclein in susceptible neurons. α-Synuclein fibril activity in cortical brain extracts from dementia with Lewy bodies (DLB) correlates with activity in matched ventricular CSF. Elevated α-synuclein fibril activity in CSF corresponds to reduced survival in DLB. α-Synuclein fibril particles amplified from cases with high fibril activity show superior templating in the formation of new inclusions in neurons relative to the same number of fibril particles amplified from DLB cases with low fibril activity. Our results highlight a previously unknown broad heterogeneity of fibril-templating activities in DLB that may contribute to disease phenotypes. We predict that quantitative assessments of fibril activities in CSF that correlate to fibril activities in brain tissue will help stratify patient populations as well as measure therapeutic responses to facilitate the development of α-synucleintargeted therapeutics.

High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease

“…It remains undetermined whether assay kinetic parameters or end-point dilution data can provide information about disease severity, clinical features, or clinical subtypes, but our results suggest that the quantitation will require additional statistical power and careful normalization. There have been efforts to standardize the assay, and one approach relies on stabilized ultra-short fibrils to act as a reference standard of known concentration and kinetics to guide interpretation of biologic samples [ 47 ]. We provide preliminary data that there may be clinical information to glean from αSyn-SAA beyond the diagnostic result.…”

α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?

“…Differences in seeding capacity do not only exist between individual synucleinopathies. High heterogeneity in fibril templating activity has also been reported in CSF and brain extracts exclusively from DLB patients, which may be a contributing factor to the variable disease phenotypes [108].…”

The Effects of Statins on Neurotransmission and Their Neuroprotective Role in Neurological and Psychiatric Disorders

“…The mechanisms described above are illustrated in Figure 3. It is important to emphasize that the last two described mechanisms concerning oxysterols and the deposition of α-synuclein are responsible for neurodegeneration not only within dopaminergic neurons, but also within other types of neurons, which may result in the occurrence of diseases such as AD [58,59] or Lewy body dementia (LBD) [60].…”

“…This effect is mainly focused on inhibiting the release of pro-inflammatory cytokines and the activation of nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) cells [61]. It has also been proven in cell models that simvastatin, by inhibiting It is important to emphasize that the last two described mechanisms concerning oxysterols and the deposition of α-synuclein are responsible for neurodegeneration not only within dopaminergic neurons, but also within other types of neurons, which may result in the occurrence of diseases such as AD [58,59] or Lewy body dementia (LBD) [60].…”