Defined α-synuclein prion-like molecular assemblies spreading in cell culture

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alpha-synuclein (α-syn) aggregation is central to synucleinopathies like Parkinson disease.
• Evidence suggests intercellular transfer of α-syn contributes to disease pathogenesis.

Purpose of the Study:

• To investigate if recombinant human α-syn amyloids can induce prion-like aggregation of endogenous α-syn in neuronal cells.
• To assess the role of endogenous α-syn in aggregate formation.

Main Methods:

• Utilized a methodology for obtaining synthetic mammalian prions.
• Exposed human neuroblastoma SH-SY5Y cells to human α-syn amyloid fibrils.
• Observed aggregation of endogenous α-syn.

Main Results:

• A single exposure to α-syn amyloid fibrils was sufficient to induce endogenous α-syn aggregation.
• Endogenous wild-type α-syn was adequate for aggregate formation; overexpression was not necessary.
• Aggregates formed from endogenous α-syn accumulated over multiple cell passages.

Conclusions:

• Compelling evidence shows endogenous α-syn accumulates in cell culture following exposure to exogenous α-syn amyloid fibrils.
• This prion-like seeding model using α-syn amyloid fibrils is a valuable tool for therapeutic screening of pathogenic α-syn aggregates.