α-Synuclein strains target distinct brain regions and cell types

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Synucleinopathies, including Parkinson's disease and multiple system atrophy, exhibit clinical and pathological heterogeneity.
• This diversity is hypothesized to arise from distinct strains of aggregated alpha-synuclein (α-synuclein), similar to prion diseases.

Purpose of the Study:

• To investigate whether different α-synuclein strains induce distinct diseases in a mouse model.
• To determine if α-synuclein strains propagate in a prion-like manner.

Main Methods:

• Inoculation of transgenic mice with various strains of recombinant or brain-derived α-synuclein aggregates.
• Detailed analysis of clinical signs, disease onset, α-synuclein deposit morphology, aggregate conformation, and cellular targeting.
• Serial passaging of induced aggregates to assess strain stability.

Main Results:

• Inoculation with different α-synuclein strains produced clinically and pathologically distinct diseases in mice.
• Strain-specific differences were observed in neurological symptoms, disease progression, α-synuclein deposit characteristics, and conformational properties.
• Distinct strains selectively targeted specific brain cell populations, mirroring human synucleinopathies.
• Strain characteristics remained stable after serial passaging, indicating prion-like templating.

Conclusions:

• Pathogenic α-synuclein aggregates exhibit strain-like properties, analogous to prions.
• Disease heterogeneity in synucleinopathies is likely driven by distinct α-synuclein strains.
• This finding provides a mechanistic explanation for the varied clinical presentations of synucleinopathies.