α-synuclein strains that cause distinct pathologies differentially inhibit proteasome

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Abnormal alpha-synuclein aggregation is linked to various diseases and spreads similarly to prions.
• The relationship between prion strain structure and disease phenotype is known, but α-synuclein strain-specific pathologies remain unclear.

Purpose of the Study:

• To investigate if different α-synuclein aggregate strains cause distinct pathologies.
• To explore the seeding and propagation abilities of two α-synuclein fibril types in vivo and in vitro.

Main Methods:

• Generation of two distinct α-synuclein fibril strains from identical monomers.
• Seeding and propagation studies in mice and primary-cultured neurons.
• Analysis of protein aggregation, proteasome activity, and protein complex co-precipitation.

Main Results:

• Two α-synuclein strains were successfully generated, differing in their ability to induce phosphorylated and ubiquitinated aggregates.
• One α-synuclein strain inhibited proteasome activity and co-precipitated with the 26S proteasome complex.
• Structural differences in the C-terminal region of α-synuclein strains correlated with varying effects on proteasome activity.

Conclusions:

• Structural variations in α-synuclein aggregates (strains) can lead to distinct pathological outcomes.
• α-synuclein strains differentially impact cellular proteasome function, offering a molecular mechanism for varied pathologies.
• This research provides insights into the pathogenesis of α-synucleinopathies.