Abstract
Backgroundα-Synuclein (α-syn) plays a central role in the pathogenesis of synucleinopathies, a group of neurodegenerative disorders that includes Parkinson disease, dementia with Lewy bodies and multiple system atrophy. Several findings from cell culture and mouse experiments suggest intercellular α-syn transfer.ResultsThrough a methodology used to obtain synthetic mammalian prions, we tested whether recombinant human α-syn amyloids can promote prion-like accumulation in neuronal cell lines in vitro. A single exposure to amyloid fibrils of human α-syn was sufficient to induce aggregation of endogenous α-syn in human neuroblastoma SH-SY5Y cells. Remarkably, endogenous wild-type α-syn was sufficient for the formation of these aggregates, and overexpression of the protein was not required.ConclusionsOur results provide compelling evidence that endogenous α-syn can accumulate in cell culture after a single exposure to exogenous α-syn short amyloid fibrils. Importantly, using α-syn short amyloid fibrils as seed, endogenous α-syn aggregates and accumulates over several passages in cell culture, providing an excellent tool for potential therapeutic screening of pathogenic α-syn aggregates.
Highlights
Background αSynuclein (α-syn) is a key player in the pathogenesis of a group of neurodegenerative diseases defined as synucleinopathies, including Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)
To test whether the same process may be induced in the non-transfected human SH-SY5Y cell line we applied different α-syn fibril assemblies to the cell culture
This is one reason why we focused on immortalized cell lines, as they yield more homogenous cell preparations, cells can be passaged for long periods, and they harbor a sufficient quantity of samples for biochemical analyses
Summary
Synuclein (α-syn) is a key player in the pathogenesis of a group of neurodegenerative diseases defined as synucleinopathies, including Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). The discovery that aggregated α-syn is the major component of Lewy bodies (LBs) [1] indicates a role of α-syn in PD. Neurons containing LBs are the hallmark of PD and DLB, whereas in MSA α-syn is deposited in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs) [2,3,4]. In its aggregated form, α-syn is enriched in β-sheet structure, orderly organized into oligomers or amyloid fibrils [5]. Many amyloid proteins are characteristic of specific neurodegenerative disorders, for instance Alzheimer disease (AD) and prion diseases.
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