Co-infection with two α-synuclein strains reveals novel synergistic interactions

Area of Science:

• Neuroscience
• Protein Misfolding Diseases
• Prion Biology

Background:

• Synucleinopathies like Parkinson's disease involve misfolded alpha-synuclein forming Lewy bodies or glial cytoplasmic inclusions.
• The prion strain hypothesis suggests protein conformation dictates disease type.
• Previous work identified a novel alpha-synuclein strain with mixed pathology.

Purpose of the Study:

• To investigate potential interactions and competition between different alpha-synuclein strains in vivo.
• To explore if co-infection by alpha-synuclein strains influences disease progression.

Main Methods:

• Utilized a prion strain interference model in TgM83+/- mice.
• Inoculated mice with mouse-passaged multiple system atrophy (MSA) strain, followed by recombinant preformed fibrils (PFFs) at varying intervals.
• Assessed neuroinvasion and disease incubation periods.

Main Results:

• Alpha-synuclein PFFs showed variable neuroinvasion based on monomer source.
• Co-inoculation of MSA and PFF strains resulted in a synergistic effect.
• Observed decreased incubation periods and presence of the MSA strain in the brain.

Conclusions:

• Two distinct alpha-synuclein strains can synergize to accelerate clinical disease progression.
• This synergy represents a novel finding in studies of mixed prion-like infections.
• Findings have implications for understanding the complex pathogenesis of synucleinopathies.