AD/PD 2026 | Novel synuclein mutations and their potential impact in Parkinson’s disease
Tiago Outeiro, PhD, University Medical Center Göttingen, Göttingen, Germany, and University of Algarve, Faro, Portugal, discusses the identification of novel synuclein mutations and their potential impact in Parkinson’s disease. Prof. Outeiro explains that his team has studied the G14R and K50N substitutions, and notes that this knowledge can inform strategies to prevent aggregation, potentiate normal function, or interfere with binding to other proteins or membranes. This interview took place at the AD/PD™ 2026 International Conference on Alzheimer’s and Parkinson’s Diseases in Copenhagen, Denmark.
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Transcript
So working with colleagues in Germany and in Austria that identified new patients that they sequenced and found to carry novel synuclein mutations that had not been identified before, this was the motivation for us to go deeper into this topic. And so we reported last year with a group of Brit Mollenhauer, one mutation that is K50N substitution, an amino acid substitution. And with the Austrian group of Christof Brücke and Alexander Zimprich, we reported another mutation that is the G14R substitution...
So working with colleagues in Germany and in Austria that identified new patients that they sequenced and found to carry novel synuclein mutations that had not been identified before, this was the motivation for us to go deeper into this topic. And so we reported last year with a group of Brit Mollenhauer, one mutation that is K50N substitution, an amino acid substitution. And with the Austrian group of Christof Brücke and Alexander Zimprich, we reported another mutation that is the G14R substitution. So what is interesting is that the G14R was found in a patient that did not present typical Parkinson’s symptoms. It looked like it had a frontotemporal lobar degeneration, so it did not present with typical Parkinson’s. But then when neuropathologists looked at the brain, they found atypical alpha-synuclein pathology. So not the typical Lewy bodies, but different types of synuclein accumulations that were intriguing. We didn’t know why that was happening with this particular form of synuclein. And so we then studied this mutation in vitro. We produced the protein recombinantly in the laboratory. We expressed it in cells. We tested it in primary neuronal cultures. And we were able to find how this protein behaves compared to the wild type. And we found many differences that we reported in the recent study. For the K58N, the patient is still alive, fortunately. So we don’t have the brain tissue. We don’t know how it behaves in the human brain, but we also reported some differences in the behavior of the K58N compared to the wild type. So we’re learning about new features, new regions of the protein that may be important for regulating both its biology as well as its pathobiology. The reason we are interested in these mutations is because by learning what they do in different regions of the protein, this gives us information both about the biology and as well as the pathobiology. And having this information allows us to think about ways to interfere with this protein in ways that could, for example, prevent aggregation, potentiate its normal function, interfere with the binding to other proteins or membranes. So we need this basic knowledge to understand the biochemistry of the protein so that we can really rationally design therapies and eventually also biomarkers.
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