Researchers at Tel Aviv University (TAU) in cooperation with three major Israeli medical centers have developed a new method for detecting protein aggregation in cells, a hallmark of Parkinson’s disease. The technology can enable diagnosis up to 20 years before the first motor symptoms appear, facilitating treatment or even prevention of the severe disease, which is currently incurable.

The novel approach is based on super-resolution microscopy combined with computational analysis, allowing for precise mapping of the aggregates’ molecules and structure. The method can be used to identify early signs and enable preventive treatment in young people at risk for developing Parkinson’s later on in their lives. In the future, the technology may also be adapted for early diagnosis of other neurodegenerative diseases, including Alzheimer’s.

The study was led by Professor Uri Ashery and PhD candidate Ofir Sade from the School of Neurobiology, Biochemistry & Biophysics at the George S. Wise Faculty of Life Sciences, the Sagol School of Neuroscience, and the Faculty of Medical and Health Sciences at TAU. Collaborating hospitals were the Tel Aviv Sourasky (Ichilov), Sheba, and Meir Medical Centers. The paper was published on September 3, 2024, in Frontiers in Molecular Neuroscience, and the research was supported in part by The Aufzien Family Center for the Prevention and Treatment of Parkinson’s Disease.

“Parkinson’s disease is the second most prevalent neurodegenerative disease in the world after Alzheimer’s, with about 8.5 million people with Parkinson’s living worldwide today and 1,200 new sufferers diagnosed annually in Israel,” Professor Ashery says. “The debilitating disease is characterized by the destruction of dopaminergic (dopamine producing) neurons in the brain’s Substantia Nigra area.

“Today, diagnosis of Parkinson’s disease is based mainly on clinical symptoms such as tremors or gait dysfunctions, alongside relevant questionnaires. However, these symptoms usually appear at a relatively advanced stage of the disease, when over 50% and up to 80% of the dopaminergic neurons in the Substantia Nigra are already dead. Consequently, available treatments are quite limited in their effect and usually address only motor problems.

“In this study we began to develop a research tool to enable diagnosis of Parkinson’s at a much earlier stage, when it is still treatable, and deterioration can be prevented.”

“One known feature of Parkinson’s is cell death resulting from aggregates of the alpha-synuclein protein,” Sade explains. “The protein begins to aggregate about 15 years before symptoms appear, and cells begin to die 5-10 years before diagnosis is possible with the means available today. This means that we have an extensive time window of up to 20 years for diagnosis and prevention before symptoms appear. If we can identify the process at an early stage, in people who are 30, 40, or 50 years old, we may be able to prevent further protein aggregation and cell death.”

Past studies have shown that alpha-synuclein aggregates form in other parts of the body as well, such as the skin and digestive system. In the current work the researchers examined skin biopsies from seven people with and seven people without Parkinson’s disease, provided by the Sheba, Ichilov, and Meir Medical Centers.

“We examined the samples under a unique microscope, applying an innovative technique called super-resolution imaging, combined with advanced computational analysis,” Sade says. “This enabled us to map the aggregates and distribution of alpha-synuclein molecules. As expected, we found more protein aggregates in people with Parkinson’s compared to people without the disease. We also identified damage to nerve cells in the skin, in areas with a large concentration of the pathological protein.”

With proof of concept obtained through the study, the researchers now plan to expand their work, supported by the Michael J. Fox Foundation for Parkinson’s Research.

“In this study we identified differences between tissues taken from people with and without Parkinson’s disease, using super-resolution microscopy and computational analysis,” Professor Ashery concludes. “In future studies we will increase the number of samples and develop a machine learning algorithm to spot relatively young individuals at risk for Parkinson’s. Our main target population are relatives of Parkinson’s patients who carry mutations that increase the risk for the disease. Specifically, we place emphasis on two mutations known to be widespread among Ashkenazi Jews.

“A clinical trial is already underway to test a drug expected to hinder the formation of the aggregates that cause Parkinson’s disease. We hope that in coming years it will be possible to offer preventive treatments, while tracking the effects of medications under the microscope. It is important to note that the method we have developed can also be suitable for early diagnosis of other neurodegenerative diseases associated with protein aggregates in neurons, including Alzheimer’s.”