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An interdisciplinary team from the Luxembourg Centre for Systems Biomedicine (LCSB) at the 8xav�������� of Luxembourg, together with international collaborators, established that a combination of small variations in genes regulating mitochondria, an important component of human cells, is associated with a higher risk for Parkinson’s disease. For the first time in the field, the researchers demonstrated that these genetic predictions translate into mitochondrial dysfunction in cellular models derived from Parkinson’s patients with a high polygenic risk score. Importantly, using data from a recent clinical trial for a drug targeting mitochondria, they also showed that Parkinson’s patients with high risk scores responded better to the treatment. These results, , pave the way for intelligent clinical trial designs and will have a considerable impact on precision medicine for Parkinson’s disease.

Parkinson’s disease is the fastest growing neurodegenerative disorder, affecting around 2% of the population over the age of sixty. Unravelling the complex genetic architecture of this disease remains a major challenge. While familial forms due to a single mutation account for 5 to 10% of all cases, the contribution of genetics in the remaining patients is poorly understood. Studies now suggest that a combination of common variations, called variants, in multiple genes may act as a risk factor for the disease. To explore their joint impact, polygenic risk scores have been developed by the research community in recent years.

Polygenic risk: Measuring the combined effect of multiple genetic variants

The idea is to estimate the risk associated with the sum of the different genetic variants carried by an individual. “Most common variants have little to no effect, but when combined with several others, they can become relevant to the disease,” explains Dr Patrick May, researcher in the LCSB Bioinformatics Core. He led the genetic analysis for this study together with Dr Zied Landoulsi who continues: “We use statistics from large-scale genetic studies to understand if each variant is associated with the disease or a specific trait. By adding up the estimated effects of these small changes in several genes, we can calculate a risk score and hopefully identify people with a higher likelihood of developing Parkinson’s disease.”

Additionally, for disorders that are very heterogeneous, with a wide array of genes and molecular mechanisms involved, this type of approach could be useful to stratify patients, meaning divide them into different groups, enabling precision medicine. Patients having a high polygenic risk score for genes that regulate a specific biological function could for example be more responsive to drugs targeting this specific pathway.

Identifying patients with impaired mitochondria

“It is well-known that mitochondria, the powerhouses of our cells, play a role in Parkinson’s disease. There is evidence that points to mitochondrial dysfunction as an early and causative event in the pathogenesis,” explains Prof. Anne Grünewald, head of the Molecular & Functional Neurobiology group. “So, we worked on the hypothesis that some patients may harbour a combination of variants in different nuclear-encoded mitochondrial genes that contributes to neurodegeneration.”

Working on datasets from two large and well-characterised cohorts, the and , the researchers calculated mitochondria-specific polygenic risk scores for over 14.000 patients and controls. They demonstrated that having multiple common mutations in genes regulating a specific mitochondrial pathway, namely oxidative phosphorylation (OXPHOS), is significantly associated with the disease. “These first results reinforce the idea that impaired mitochondrial respiration is a relevant aspect in Parkinson’s disease and indicate that polygenic risk scores provide a tool to genetically stratify patients, allowing us to effectively identify a subgroup of people with relevant alterations of mitochondrial function,” details Dr Giuseppe Arena, researcher in the Translational Neuroscience group and one of the first authors of this study.

Validating genetic scores in patients’ cells

Next, the researchers wanted to determine whether these specific genetic risk scores could be linked to corresponding characteristics in patient cells. They performed functional experiments in skin cells donated by participants of the Luxembourg Parkinson’s Study and in neuronal progenitors derived from these skin cells in the lab. In both cases, they observed significant differences in mitochondrial respiration between the cells of patients with high and low risk scores for the OXPHOS pathway. “For the first time in this field, our study validated the existence of profiles in the cellular models corresponding to the calculated risk scores,” underlines Dr Arena.

And testing their relevance for clinical trials

In the last part of the study, the team investigated if using polygenic risk scores for patient stratification could help identifying people who are more responsive to drugs specifically targeting mitochondria. To this end, they retrospectively classified participants from a according to the same mitochondria-specific risk scores. The trial, led by from the 8xav�������� of Sheffield and from 8xav�������� College London, focused on treatment with a compound known to rescue mitochondrial function. The results showed that patients with a high risk score responded more effectively to the treatment, further corroborating the potential of this genetic stratification approach.

“It is really exciting to see how using mitochondria-specific risk scores could allow for the selection of more homogenous patient groups for mitochondria-centred clinical trials,” highlights Prof. Anne Grünewald. “It provides an accurate tool to identify patients with altered mitochondrial function, who will benefit the most from targeted therapies. Additionally, as increased mitochondrial risk is often associated with early onset of the disease, people with very high scores could also benefit from preventive treatments in the future.”

“These results are a milestone for precision medicine in Parkinson’s disease and therefore relevant for clinicians and scientists engaged in translating fundamental research into concrete therapeutic interventions,” concludes Prof. Rejko Krüger, head of the Translational Neuroscience group and coordinator of the . “Our findings were only possible due to the comprehensive design of the Luxembourg Parkinson’s study, allowing not only for genetic screening but also functional analyses of patient-based cellular models from the same individuals. This strategy will open the door to further collaborations with new partners testing targeted compounds for slowing disease progression.”

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Reference: Giuseppe Arena, Zied Landoulsi, Dajana Grossmann, Thomas Payne, Armelle Vitali, Sylvie Delcambre, Alexandre Baron, Paul Antony, Ibrahim Boussaad, Dheeraj Reddy Bobbili, Ashwin Ashok Kumar Sreelatha, Lukas Pavelka, Nico Diederich, Christine Klein, Philip Seibler, Enrico Glaab, Thomas Foltynie, Oliver Bandmann, Manu Sharma, Rejko Krüger, Patrick May and Anne Grünewald, , Annals of Neurology, 20 May 2024.

Reference of the clinical trial: EudraCT no. 2018–001887-46

Funding: This study was supported by the (FNR) and the (DFG).

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