α-synuclein conformation may underlie neurodegenerative variability

Varying structural conformations of α-synuclein may explain how one protein can give rise to distinct forms of neurodegeneration, say researchers.

As reported in Nature, Veerle Baekelandt (KU Leuven, Belgium) and colleagues tested the effects of two previously characterised strains of α-synuclein – ribbons and fibrils – when injected into the brains of rats.

Four months after these α-synuclein strains were introduced directly into the rats’ substantia nigra, the team observed aggregates resembling Lewy bodies and Lewy neurites, confined primarily to dopaminergic cells. These aggregates were much more abundant after injection of ribbons than fibrils, and Lewy neurite-like aggregates were predominant.

By contrast, injection of α-synuclein oligomers did not lead to the formation of α-synuclein aggregates.

When the researchers induced α-synuclein overexpression in rats injected with ribbons, they also observed aggregates in oligodendroglial cells, resembling the glial cytoplasmic inclusions that occur in multiple system atrophy. This did not occur with fibrils or oligomers.

Despite the appearance of the aggregates, there was no detectable dopaminergic cell death during the 4-month follow-up. However, in combination with α-synuclein overexpression, the α-synuclein strains induced a reduction in striatal dopaminergic nerve terminal volume, with fibrils causing the largest reduction of 61%, compared with a 32% reduction for α-synuclein overexpression alone.

Rats given fibrils in combination with α-synuclein overexpression also displayed motor impairment from day 60 onwards. But injection of ribbons or oligomers did not add to the effects of α-synuclein overexpression.

“Thus, although ribbon inoculation induced more pronounced Lewy body/Lewy neurite-like inclusions, fibrils imposed the largest neurotoxic burden on the striatonigral pathway”, say Baekelandt et al.

Furthermore, fibrils were still abundant in striatal dopaminergic axons 4 months after injection, at a level at least fourfold greater than that of ribbons, while oligomers were barely detectable.

In an accompanying commentary, Seung-Jae Lee (Seoul National University College of Medicine, Korea) and Eliezer Masliah (University of California San Diego, La Jolla, USA) raise the possibility that “the blood of people with Parkinson’s disease, dementia with Lewy bodies or multiple system atrophy might contain specific strains of α-synuclein that can serve as biomarkers for these diseases.”

The researchers also showed that repeated intravenous injection of rats with these α-synuclein strains was followed by their appearance in the central nervous system. This indicates that “strains might not have to be generated in the central nervous system, or even in neurons, but instead could be transported there after being generated in the periphery”, say Lee and Masliah.

However, they caution that more work is needed to definitely prove that these α-synuclein strains propagate after seeding, rather than the seeding itself causing inflammation and other local changes that facilitate protein misfolding and neurodegeneration.

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