A-synuclein prion strains differentially adapt after passage in mice

Area of Science:

• Neuroscience
• Biochemistry
• Prion Biology

Background:

• Synucleinopathies, including multiple system atrophy (MSA) and Lewy body diseases (LBDs), arise from misfolded α-synuclein conformations.
• Peripheral onset of autonomic failure can progress to MSA or LBD.
• Prion protein (PrP) neuroinvasion can lead to novel strain variants, but α-synuclein strain adaptation remains unclear.

Purpose of the Study:

• To investigate if α-synuclein prion properties are retained or adapted after neuroinvasion.
• To compare α-synuclein prion characteristics following intracranial and sciatic nerve inoculation in a mouse model.

Main Methods:

• TgM83+/- mice expressing mutant human α-synuclein (A53T) were inoculated with a mouse-passaged MSA sample either intracranially (i.c.) or into the sciatic nerve (sc.n.).
• Biochemical and biological properties of α-synuclein prions in terminal mouse brains were analyzed.
• Infectivity profiles of primary and secondary MSA samples were assessed in α-syn140-YFP cells.
• A53T preformed fibrils were used for intracranial inoculation to study strain selection.

Main Results:

• Both i.c. and sc.n. transmissions yielded pathogenic α-synuclein with similar properties.
• Passaged MSA samples exhibited altered infectivity profiles compared to the initial sample, indicating prion adaptation.
• Mouse passage exerted selective pressure on α-synuclein prions, leading to the emergence of a sub-population of conformations.

Conclusions:

• α-synuclein prions adapt during initial passage in TgM83+/- mice.
• Conformational selective pressures similar to those affecting PrP prion replication also influence α-synuclein prion replication.
• These findings highlight the dynamic nature of α-synuclein prion strains in vivo.