Neurodegeneration

Aggregates feel the strain

Aggregates of α-synuclein protein can form in various cell types and cause different neurodegenerative disorders. The existence of strains with distinct structural conformations might explain this variability. See Letter p.340

Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are devastating, progressive, age-related neurodegenerative disorders that are characterized by the accumulation of clumps of α-synuclein protein in brain cells1. These diseases, dubbed synucleinopathies, can be differentiated from one another by the distinct anatomical patterns and cell types in which α-synuclein is deposited2. On page 340 of this issue, Peelaerts et al.3 propose that different 'strains' of α-synuclein, which adopt different structural conformations, might explain this variability.

According to current models, deposits of α-synuclein are first laid down in the synaptic connections between neurons during the early stages of synucleinopathy4. Deposition later spreads to other sites: to neuronal cell bodies, where they form aggregates called Lewy bodies; to neuronal projections called axons and dendrites, forming aggregates called Lewy neurites; and to cells known as oligodendrocytes that support and insulate axons, forming aggregates called glial cytoplasmic inclusions (GCIs)2.

These GCIs are the predominant deposits in people with multiple system atrophy2. Lewy bodies and Lewy neurites are characteristic of both Parkinson's disease and dementia with Lewy bodies — although the patterns in which the proteins spread vary between these two diseases. Furthermore, patterns of α-synuclein deposition, and consequently clinical symptoms, can vary between individual cases of the same disease5. But the reasons underlying this variability have remained unclear.

Synucleinopathies have several features in common with prion diseases, which are neurodegenerative diseases caused by the accumulation of misfolded prion protein in the brain. For example, the symptoms, biological abnormalities and incubation times of both types of disease are variable. In prion diseases, variability between individuals depends on the conformation adopted by aggregates of prion protein. Aggregates of a specific conformation are thought to propagate throughout the brain by inducing normal prion proteins to clump together into misfolded aggregates of the same conformation — a concept known as 'seeded aggregation'. Evidence suggests6 that aggregates of α-synuclein and other neurodegeneration-associated proteins spread through brain cells in a similar way, which might explain the varied patterns in which deposition spreads.

In support of this hypothesis, two distinct aggregates of α-synuclein, fibrils and ribbons, have been characterized7. These aggregates faithfully propagate their structural features through seeding, and induce different abnormalities in cultured cells. Following up on these findings, Peelaerts et al. investigated whether ribbons and fibrils are genuine protein strains by testing whether they cause different symptoms and biological changes in animals. The authors injected rat brains with four different types of α-synuclein: ribbons; fibrils; homogenized brain samples from mice that produce a human α-synuclein aggregate; and short strings of abnormal α-synuclein protein called oligomers, which might give rise to the more complex ribbon and fibril structures8. They then analysed α-synuclein deposition in these animals.

Ribbons caused more deposition than other types of α-synuclein. By contrast, and consistent with a study in mice9, fibrils more potently promoted other hallmarks of neurodegenerative disease, such as degeneration of dopamine axons in the striatum region of the brain and deficits in motor function. Fibrils were more stable than ribbons, which generated structures resembling Lewy bodies and Lewy neurites. These findings indicate that the aggregates induced by ribbons and fibrils are indeed distinct. When they injected ribbons into rats that had been engineered to produce too much α-synuclein, Peelaerts et al. observed the generation of GCIs, but inoculation with fibrils did not have this effect. Together, these results suggest that different synucleinopathies are defined by different strains of α-synuclein aggregate (Fig. 1).

Figure 1: Structural variability and disease.
figure1

The protein α-synuclein can adopt different structural conformations. Monomers of the protein interact with each other to form complexes called oligomers, which in turn are converted into either fibrils or ribbons. Furthermore, it is possible that fibrils are converted into ribbons. Peelaerts et al.3 report that the different conformations have different properties: fibrils primarily cause neurodegeneration and behavioural defects when injected into the brains of rats, whereas ribbons mostly cause the accumulation of protein aggregates called Lewy bodies, Lewy neurites and glial cytoplasmic inclusions (GCIs). Structures are not to scale.

The researchers also demonstrated that intravenous inoculations of aggregates that had been preformed in vitro led to the deposition of α-synuclein in the central nervous system of animals. Blood contains relatively large amounts of α-synuclein10, so this result suggests that, if changes in this peripheral system affect conformations of α-synuclein, this could translate into specific neuronal abnormalities.

Peelaerts and colleagues' study has several implications. First, neurodegeneration and behavioural deficits seem to be associated primarily with fibrils, whereas the formation of Lewy bodies, Lewy neurites and GCIs is associated more with ribbons. Second, the distinct patterns of α-synuclein deposition observed after cerebral inoculations of fibrils and ribbons suggest that different strains of aggregate are the explanation for the variability of synucleinopathies. Third, 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.

Despite Peelaerts and colleagues' findings, and advances made by other groups11, it remains to be definitively proved that injected aggregates can amplify through seeding. An alternative explanation is that the injected aggregates lead to changes such as inflammation in the microenvironment of the brain region into which they are injected, and that this could eventually result in distinct abnormalities. Synucleinopathies are accompanied by brain inflammation in humans, and the authors showed that injecting different α-synuclein aggregates caused brain inflammation to different extents. In vitro amplification and structural characterization of the amplified aggregates from brain tissues could provide the much-needed proof of aggregate seeding12. Whether ribbons or fibrils are sustained if brain tissue from the infected animal is injected into another animal also needs further validation to confirm that these aggregates are indeed strains.

Can strains generated in the blood induce α-synuclein aggregation in the brain and cause neurodegeneration? Peelaerts and colleagues' results indicate that this is a possibility. The study also suggests 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 results raise the question of whether α-synuclein pathology can be transmitted between humans through blood. So far, there is no evidence for such a phenomenon, but future studies should address this question.Footnote 1

Notes

  1. 1.

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Correspondence to Seung-Jae Lee or Eliezer Masliah.

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Lee, S., Masliah, E. Aggregates feel the strain. Nature 522, 296–297 (2015). https://doi.org/10.1038/nature14526

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