Test in development aims to spot tiny alpha-synuclein fibrils early

Goals include detecting protein in blood samples, helping with drug development

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A new test that can detect extremely small concentrations of clumped alpha-synuclein may help to detect Parkinson’s disease and related disorders in early stages.

The test, reportedly able to spot single protein fibrils, was described in the study, “Toward the quantification of [alpha]-synuclein aggregates with digital seed amplification assays,” published in PNAS.

“This work is an important step toward our goal to develop a method to detect and quantify a key marker of Parkinson’s disease to help clinicians identify patients much earlier, and thus keep [Parkinson’s] and related neurodegenerative disorders much more effectively at bay,” David Walt, PhD, a study co-author at Brigham and Women’s Hospital, said in a press release.

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Test detected alpha-synuclein fibrils at levels measured in picograms

Alpha-synuclein is a protein found naturally in the brain. But with Parkinson’s, the protein clumps into aggregates or fibrils that are toxic to nerve cells and are thought to play a major role in driving the disease’s progression.

Alpha-synuclein clumps also are characteristic of some forms of atypical parkinsonism, including Lewy body dementia and multiple system atrophy (MSA). Collectively, these disorders are referred to as synucleinopathies.

Researchers, led by those at Brigham and Women’s and Harvard University, wanted to make a lab test that would allow them to measure alpha-synuclein aggregates at very low concentrations.

“The quantification and characterization of aggregated [alpha]-synuclein in clinical samples offer immense potential toward diagnosing, treating, and better understanding neurodegenerative synucleinopathies,” they wrote.

The test, using what is called digital seed amplification assays or digital SAAs, relies on the fact that, when one alpha-synuclein clump forms, it prompts nearby alpha-synuclein proteins to also aggregate. It basically works by segregating individual alpha-synuclein fibers into tiny compartments, then using them as seeds that generate larger and detectable clumps.

Researchers showed that this approach could detect alpha-synuclein fibrils at concentrations as low as 4 picograms per milliliter (one picogram is equal to one-trillionth of a gram). They also showed it could detect these toxic protein clumps in brain samples from people with Parkinson’s or MSA, as well as in these patients’ cerebrospinal fluid (the fluid that surrounds the brain and spinal cord).

“Using brain tissue and cerebrospinal fluid samples collected from patients with Parkinson’s Disease and multiple system atrophy, we demonstrated that the assay can detect endogenous pathological [alpha]-synuclein aggregates,” the scientists wrote. Endogenous means originating within a living organism, while pathological refers to things that are disease causing or involving.

Hoping to test for Parkinson’s toxic alpha-synuclein in a blood sample

The team now wants to develop this technology with the goal of detecting alpha-synuclein clumps in more clinically relevant samples like blood, which could serve as the basis for diagnostic tests.

“Our digital SAAs present a critical technological advance with the potential to turn pathological [alpha]-synuclein into an early biomarker for this class of neurodegenerative diseases,” said Tal Gilboa, PhD a postdoctoral researcher in Walt’s lab and the study’s co-first author. “But work remains to be done. Our current strategies worked well on brain tissue samples from [Parkinson’s] and MSA patients, but there’s room to improve their sensitivities so that we can meet the criteria for clinical diagnostic testing, and, hopefully, detect [alpha]-synuclein fibrils in blood and other biological fluids.”

The scientists also think this technology could be a useful tool for testing potential therapies that aim to treat Parkinson’s by stopping alpha-synuclein from forming toxic clumps.

“Having a biomarker that we can quantify could help us identify new drug candidates, and test their effects in more targeted patient cohorts at early stages of the diseases,” Walt said.

“Applying the assays as a drug discovery tool could facilitate the search for promising drug candidates that more efficiently inhibit fibril formation, or even help us identify new drug targets … Using this system flexibly could help us better understand how we can constrain aggregate growth,” said Zoe Swank, PhD, the study’s other first author and also a postdoctoral researcher in Walt’s lab.