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Test distinguishes Parkinson's disease from related condition

From NIH Research Matters

A protein called alpha-synuclein plays a major role in Parkinson’s disease as well as other brain disorders. In these conditions, the protein misfolds and aggregates (collects and sticks together) to create clumps called Lewy bodies within cells. Lewy bodies are thought to be toxic to certain neurons in the brain.

cryo-electron tomography reconstruction of alpha-synuclein fibrilsUsing a technique called cryo-electron tomography, the researchers created 3D reconstructions of alpha-synuclein fibrils from people with PD (top) and MSA (bottom) that illustrate the differences in twisting. The boxes show magnified views. Shahnawaz et al., Nature.

Parkinson’s disease and another disease involving alpha-synuclein, called multiple system atrophy (MSA), are particularly difficult to tell apart based on early symptoms. While there is no cure for either, the two diseases require different treatments to keep people with the conditions healthy as long as possible.

Researchers led by Dr. Claudio Soto from UTHealth in Houston used a test called protein misfolding cyclic amplification (PMCA) to detect small amounts of alpha-synuclein aggregates in cerebrospinal fluid (CSF). PMCA works by exposing regular alpha-synuclein protein to samples from patients that might contain misfolded alpha-synuclein. If present, the misfolded protein amplifies itself by misfolding regular alpha-synuclein. This copying process allows detection and analysis of the misfolded proteins, which aggregate and assemble into thin, twisted fibrils. Such fibrils form a large component of Lewy bodies.

Previous studies suggested that the fibrils produced in people with Parkinson’s disease and MSA may adopt slightly different shapes. To see if PMCA could be used to distinguish the different fibrils, the scientists tested CSF samples from people known to have Parkinson’s disease, MSA, and other neurological diseases not related to alpha-synuclein.

The research was funded in part by NIH’s National Institute on Aging (NIA) and National Institute of Neurological Disorders and Stroke (NINDS). Results were published on Feb. 13, 2020, in Nature.

The scientists confirmed that the PMCA products from people with Parkinson's disease and MSA reacted differently with a fluorescent dye. They showed other differences as well, such as their ability to resist degradation by molecules that cut proteins. In studies looking at the structure of the alpha-synuclein fibrils, the team found that the fibrils twisted differently between Parkinson's disease and MSA.

When tested in samples from 94 people with Parkinson’s disease and 75 with MSA, PMCA was able to tell the difference between the two diseases with about 95% accuracy. No signal was seen when samples were tested from 56 people with other neurological diseases not related to alpha-synuclein.

“By amplifying the abnormal [alpha synuclein] aggregates, we can detect with high efficiency which disease the patient has,” Soto says. “This has huge implications both for accurate diagnosis and clinical care of the patient, and the development of new specific treatments for both diseases.”

—by Sharon Reynolds for NIH Research Matters

This research was funded in part by NIA grants R01AG061069 and RF1AG055053.

Reference: Shahnawaz M, et al. Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. Nature. 2020; 578(7794):273-277. doi: 10.1038/s41586-020-1984-7.