Objective: We hypothesized that the clinical heterogeneity found in Lewy body disorders is a consequence of the molecular diversity of αSyn between different patients as well as different brain regions.

Background: Lewy body disorders (LBD) are clinically heterogeneous and are characterized by deposition of misfolded α-synuclein (αSyn). Although the distribution of αSyn aggregates correlates with the predominant clinical features, the burden of pathology does not fully explain the observed differences in clinical presentation and rate of disease progression.

Method: Using an ultra-sensitive seeding assay, we conducted a multi-regional evaluation of αSyn seeding in 8 different brain regions from 30 LBD patients with different clinical subtypes and disease durations. To further validate these results and to determine factors that drive seeding heterogeneity in LBD, we integrated our seeding assay data with in vitro toxicity assays, neuropathological and biochemical examinations and a complete proteomic profiling of the substantia nigra from 5 patients with a protracted course and 5 patients with rapid disease progression.

Results: When the αSyn seeding was compared across the clinical phenotypes, the hippocampal αSyn derived from the patients with a cognitive-predominant phenotype showed a significantly higher seeding capacity than the ones derived from the patients with a motor-predominant phenotype, whereas the nigral αSyn derived from the latter patients showed a significantly higher capacity than the ones derived from patients with a cognitive-predominant phenotype. Furthermore, the αSyn derived from the patients with a rapid disease progression (<3 years) displayed a higher seeding capacity compared to those patients with a protracted disease course (>10 years).
Our results also indicate that a higher αSyn seeding capacity is linked to higher degree of neuronal toxicity and a different biochemical profile. The proteomic data revealed evidence of a significant disruption in the mitochondrial processes and lipid metabolism in the rapidly progressive cases compared to those with a protracted progression.

Conclusion: These observations suggest that distinct molecular populations of αSyn may contribute to the different phenotypes and progression rates seen in LBD patients and imply that effective therapeutic strategies might need to consider not a singular but a cloud of differently misfolded αSyn species.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/%ce%b1-synuclein-molecular-behavior-and-proteomic-profiling-distinguish-subtypes-of-lewy-body-disorders/