α-Synuclein strains cause distinct synucleinopathies after local and systemic administration

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Misfolded protein aggregates characterize neurodegenerative diseases like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).
• Alpha-synuclein (α-SYN) aggregates are the hallmark of synucleinopathies, with distinct cellular localization (neuronal vs. glial) correlating with disease phenotypes.
• The concept of α-SYN 'strains' with varying structures offers a potential explanation for the diverse clinical and pathological presentations within synucleinopathies.

Purpose of the Study:

• To investigate whether distinct α-SYN strain conformations and their seeding propensities lead to differential histopathological and behavioral outcomes.
• To determine the in vivo amplification and pathogenic potential of structurally defined α-SYN assemblies (oligomers, ribbons, fibrils).
• To examine the ability of α-SYN assemblies to cross the blood-brain barrier (BBB) and distribute within the central nervous system (CNS).

Main Methods:

• In vivo injection of structurally characterized α-SYN assemblies (oligomers, ribbons, fibrils) into the rat brain.
• Assessment of histopathological changes, including protein aggregation and cell death.
• Evaluation of behavioral deficits, specifically motor impairment.
• Intravenous administration of α-SYN assemblies to study BBB crossing and CNS distribution.

Main Results:

• Structurally distinct α-SYN strains were shown to amplify in vivo, inducing strain-specific histopathological and behavioral phenotypes.
• α-SYN fibrils were identified as a major toxic strain, causing progressive motor impairment and neuronal cell death.
• α-SYN ribbons induced a unique histopathological profile, exhibiting features of both Parkinson's disease and multiple system atrophy.
• Intravenous injection demonstrated that α-SYN assemblies can cross the blood-brain barrier and enter the CNS.

Conclusions:

• Distinct α-SYN strains possess differential seeding capacities, leading to specific pathological outcomes and neurotoxic effects.
• The conformation of α-SYN assemblies is a critical determinant of the resulting disease phenotype in synucleinopathies.
• These findings support the 'strain hypothesis' as an explanation for the diverse clinicopathological spectrum of synucleinopathies and highlight potential therapeutic targets.