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

Area of Science:

• Neuroscience
• Protein Misfolding Diseases
• Prion Biology

Background:

• Synucleinopathies like Lewy body disease (LBD) and multiple system atrophy (MSA) involve misfolded alpha-synuclein forming distinct pathological structures (Lewy bodies or glial cytoplasmic inclusions).
• The prion strain hypothesis suggests protein conformation dictates disease type, with distinct alpha-synuclein strains identified in LBD and MSA.
• A novel alpha-synuclein strain was recently found in a Parkinson's disease with dementia patient exhibiting both LB and GCI-like pathology, raising questions about strain interactions.

Purpose of the Study:

• To investigate if two distinct alpha-synuclein strains can interact within a host and potentially compete.
• To explore the impact of strain interactions on disease progression and therapeutic strategies for synucleinopathies.
• To test the hypothesis of strain interference/competition using a mouse model of alpha-synucleinopathy.

Main Methods:

• Utilized a strain interference superinfection model by inoculating TgM83^+/- mice with mouse-passaged MSA (slower strain) via sciatic nerve.
• Administered recombinant preformed fibrils (PFFs, faster strain) at varying intervals (30%, 45%, 60%) after the initial MSA inoculation.
• Assessed neuroinvasion, disease onset, and pathological evidence of both strains in the brains of affected mice.

Main Results:

• Contrary to prion models, the two alpha-synuclein strains exhibited a synergistic effect, accelerating neuroinvasion.
• Disease onset was significantly shortened in mice co-inoculated with both strains compared to MSA inoculation alone.
• Brains of terminal mice showed evidence of both PFF and mouse-passaged MSA strains, confirming co-existence and interaction.

Conclusions:

• Two alpha-synuclein strains can synergize to accelerate disease progression, a novel finding in mixed infection studies.
• This synergistic interaction has significant implications for understanding synucleinopathy pathogenesis and clinical presentation in patients with co-pathologies.
• The findings expand the understanding of prion strain biology's role in disease and highlight challenges for developing targeted therapeutics.