Mitochondria targeting RNAs involved in oxidative stress and Parkinson’s Disease

Parkinson’s disease is the most common neurological disease in humans. Currently 4000 people suffer from Parkinson’s disease in Luxembourg; however, this number is expected to increase in the coming years. Normal bodily movements become impaired during Parkinson’s and the effect of the disease is different for men and women. Although treatments exist, there is still no cure for the disease. Even the diagnosis of Parkinson’s is challenging, as the signs and symptoms of the disease often get mistaken for other age-related problems.
The mitochondria are very important cellular elements in the human body. Their main goal is to produce energy for our cells but they also produce reactive oxygen species. When the mitochondria become damaged or die, this places cells under heightened states of stress known as oxidative stress.    Oxidative stress plays a key role in many age-related disorders including Parkinson’s disease. Three genes within our DNA (called SOD2, PARK2 and PINK1) control many functions that mitochondria perform and also coordinate the removal of damaged mitochondria and oxidative stress. In Parkinson’s disease, the mitochondria no longer function correctly which leads to the worsening of the disease.
Since RNA-based vaccines were used during the COVID pandemic, more and more research has shown that RNA-based medicine could be used to treat other diseases, including mitochondrial diseases. A sub-class of RNA known as non-coding RNAs are involved in many diseases. Several non-coding RNAs directly target SOD2, PARK2, PINK1 and the machinery within the mitochondria during non-disease and disease states. To date, the role these mitochondria-targeting non-coding RNAs play in mitochondrial damage, oxidative stress and Parkinson’s disease is poorly understood – as is their ability to be detected in the blood of patients or to be used as new treatments for Parkinson’s disease.
The overall aim of this project is to better understand the role of these non-coding RNAs that target PARK2 and/or PINK1 during damage to mitochondria that leads to oxidative stress and Parkinson’s disease and to assess whether we can measure them in blood and use them as new treatments for Parkinson’s. We plan to select non-coding RNA targets that can interact with PARK2 and/or PINK1 from previous work in the lab and through the recycling and re-analysis of large sets of previously generated RNA sequencing data – one such set of data is the Parkinson’s Progressive Markers Initiative (PPMI) study: one of the largest resources of Parkinson’s disease in the world. To better understand the function and role of these non-coding RNAs in Parkinson’s disease, we will change their expression (up or down) and look at whether that affects how cells grow and how mitochondria function. To see whether we could use these RNAs as biomarkers and to see whether any differences exist between men and women, we will measure them in the blood of patients from two European cohorts; 1 from Luxembourg (comprising a total of 638 samples) and 1 from Spain (comprising a total of 200 samples). The expected outcomes from this project include: the training of a PhD student, the discovery of mitochondria-targeting non-coding RNAs involved in Parkinson’s disease and whether they could be used as blood based biomarkers and/or new treatments. This innovative and clinically relevant project will increase our understanding of mitochondrial damage, oxidative stress and Parkinson’s disease taking us one step closer to more accurate diagnostic and treatment alternatives.