AD/PD 2026 | The spectrum of alpha-synuclein species in Parkinson’s disease and other synucleinopathies

So in the field of Parkinson’s disease and synucleinopathies in general, we’ve thought that the Lewy bodies that we see in the brains of patients could be the culprits, the toxic species. But many years ago we started to doubt this because we see that Lewy bodies typically exist in surviving neurons. So this raised the question that perhaps other species would be more relevant, more toxic. And there has been a wealth of evidence suggesting that smaller species that we normally call oligomers or oligomeric species might indeed have stronger pathological effects. At least this is what we find in a wealth of animal and cell-based models. So we know in reality that the aggregation of alpha-synuclein, and the same could be said for tau and A-beta and any protein that aggregates, is not a uniform process. It’s actually a process that goes from functional, soluble proteins through different steps, including the formation of oligomers, protofibrils, different species we may not even be aware of, and eventually we think they form the typical fibrillar aggregates that we now can detect and characterize with current techniques like cryo-EM. So there’s great interest in understanding these other species because perhaps they will be more relevant from a pathology standpoint and they would then be better targets for therapeutic intervention. So the field has been interested in this question for a long time. Of course, we also know that there’s alternative hypotheses and that the loss of normal, soluble, physiological proteins may also contribute to disease. So there’s this idea that proteinopenia may also be important. I think it’s probably a bit of both, both proteinopathy and proteinopenia. But we need to learn more about this process.

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