MDS 2025 | Two novel alpha-synuclein missense variants identified in patients with Parkinson’s disease

So recently, my group was involved in the study of two novel missense variants in alpha-synuclein. One is the G14R that was identified in a family in Austria with some colleagues from Vienna. And the other is the mutation K58N that was identified in a patient in Germany. So the thing with these mutations is that they are very rare as most other alpha-synuclein mutations. So in this case, we cannot say they are pathogenic because we identified them in one patient for one of these cases and in two people in the other mutation, in the G14R mutation. So we cannot say they are really pathogenic. But the fact that they were identified in patients with Parkinson’s disease suggests that maybe altering the alpha-synuclein protein in the regions that are affected by the mutations can lead to detrimental consequences. And this is what we investigated in the study. So we used a variety of molecular approaches ranging from state-of-the-art cryo-EM studies to assess the structure, the fibers formed by these mutant variants, to cell models expressing these variants. And we found that, indeed, the mutants seem to change the behavior of the wild-type protein, so the protein behaves differently than the wild type, and this gives us some ideas of possible pathogenic mechanisms associated with mutations in alpha-synuclein. So it’s very important, even if we cannot say today that these mutations are pathogenic, it’s very important to study and to continue to identify mutations to understand how the protein functions.

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