New method can identify younger people at risk of Parkinson's disease

A new method for detecting toxic protein clumps made of alpha-synuclein in skin cells can help diagnose Parkinson's disease up to two decades before the onset of motor symptoms, according to a recent study.

The novel technology combines high-resolution microscopy and advanced computer-aided analysis to precisely image the molecules and structures of protein clumps in skin samples.

“In this study, we have begun to develop a research tool that will enable Parkinson's disease to be diagnosed at a much earlier stage, when the disease is still treatable and deterioration can be prevented,” said Dr. Uri Ashery, a professor at Tel Aviv University and lead researcher on the study, in a press release.

Their study “A novel super-resolution microscopy platform for the detection of cutaneous alpha-synuclein in Parkinson’s disease”, was published in Frontiers of molecular neuroscience.

Parkinson's disease is caused by the death of nerve cells (neurons) in the brain that are responsible for producing dopamine, a chemical messenger important for nerve cell communication. This death is often caused by the buildup of toxic protein clumps, or aggregates, of alpha-synuclein.

Alpha-synuclein begins to clump about 15 years before symptoms appear

Alpha-synuclein begins to form aggregates approximately 15 years before the onset of symptoms. In the period from five to ten years before diagnosis, there is significant cell death, mainly due to clinical motor symptoms. By the time symptoms appear, many dopamine-producing neurons have already died, limiting the effectiveness of available treatments.

The researchers emphasized the importance of detecting Parkinson's before protein aggregates cause such extensive cell death in the brain.

“If we can detect the process at an early stage, in people aged 30, 40 or 50, we may be able to prevent further protein aggregation and cell death,” says Ofir Sade, a doctoral student at Tel Aviv University who worked on the research.

Alpha-synuclein aggregates can also form in other parts of the body outside the brain, such as the skin and digestive system.

In the current study, researchers examined skin samples from seven Parkinson's patients and seven people without the disease (controls) from three medical centers. They then processed the samples to identify these protein aggregates.

The samples were examined using a unique microscopy technique called super-resolution microscopy. This allows researchers to capture images at nanoscale resolution, which can exceed the limits of conventional light microscopy.

The researchers then developed a user-friendly analysis platform that combines several complex computer algorithms to analyze the generated images.

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Skin samples from patients showed more alpha-synuclein aggregates

Skin samples from Parkinson's patients showed a higher number of alpha-synuclein aggregates than those from healthy controls. These aggregates were also larger and denser in Parkinson's patients.

Skin regions with an excess of alpha-synuclein aggregates also showed signs of degeneration of nerve fiber tissue.

The Michael J. Fox Foundation for Parkinson's Research is funding an extension of these initial findings in a larger study. In the next phase, the researchers will test the high-resolution microscopy and analysis platform on skin samples from 45 Parkinson's patients and 45-90 healthy volunteers.

The researchers plan to collaborate with computer scientists in these large-scale studies to correlate their findings under the microscope with motor and cognitive features of Parkinson's disease.

By increasing sample sizes and developing machine learning algorithms in future studies, researchers can identify young people at risk for the disease.

“Our primary target group is relatives of Parkinson's patients who carry mutations that increase the risk of the disease,” Ashery said. “In particular, we are focusing on two mutations that are known to be widespread among Ashkenazi Jews.”

The researchers hope that this “new molecular toolbox” can be used to quantitatively track disease progression, measure the effectiveness of disease-modifying treatments, and serve as a measurable disease marker that can be used to establish objective thresholds for Parkinson’s patients being recruited for clinical trials.

This method of microscopy and computer-assisted analysis could be helpful in the early diagnosis of other neurodegenerative diseases, such as Alzheimer's disease, which are associated with protein aggregates in brain cells.

“Our method can detect early signs and enable preventive treatment in young people who are at risk of developing Parkinson's later in life,” the researchers explained in the press release.