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At a glance:
- Scientists are working to design a new way to detect the molecular footprints of Parkinson’s disease and related neurodegenerative disorders at the earliest stages.
- Identifying the disorder before onset of symptoms could mean earlier intervention to minimize some of the nerve damage that follows.
- If affirmed in further work, the new approach could create early molecular diagnostics, improve clinical trials, and expedite drug screening.
In the earliest stages of Parkinson’s disease, the changes that eventually cause damage to neurons take place quietly in the brain long before patients show any symptoms. Without a test that can detect these changes, it’s difficult to intervene early to slow disease progression.
To address this need, Harvard Medical School researchers at Brigham and Women’s Hospital and the Wyss Institute for Biologically Inspired Engineering at Harvard University have developed a molecular test that successfully detected and quantified telltale protein clumps in tissue and fluid samples obtained from patients with Parkinson’s disease.
The test captured the presence of single ⍺-synuclein fibrils, the disease-causing proteins that are a hallmark of Parkinson’s disease and other neurodegenerative disorders collectively known as ⍺-synucleinopathies.
The team’s results are published Jan. 8 in PNAS.
Researchers note that if the reliability of the test is confirmed through further research in patients, this could enhance efforts toward more timely identification of Parkinson’s disease, a disorder currently diagnosed mainly based on medical history and clinical symptoms.
In some cases, physicians can use more sophisticated and expensive PET scans as well as analysis of cerebrospinal fluid, but these tests may not always provide a definitive diagnosis in the earliest stages of the disease, especially in patients without genetic mutations — about 90 percent of those with Parkinson’s disease.
Also, because the new test is quantitative, it could provide clinicians with an indication of disease progression, including whether drugs are effective in slowing down the march of the disease.
“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 disease and related neurodegenerative disorders much more effectively at bay,” said corresponding author David Walt, Hansjörg Wyss Professor of Biologically Inspired Engineering and professor of pathology at HMS and Brigham and Women’s.
“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 disease,” Walt said.
Worldwide, more than 10 million people have Parkinson’s disease, a neurodegenerative disorder whose incidence tends to rise as people age, a particular concern in populations where average life expectancies have been increasing in recent decades. In the U.S. alone, nearly 90,000 people are diagnosed with Parkinson’s each year. Often, by the time clinical symptoms appear, the disease has already wreaked irreversible damage in the brain.
Once refined and confirmed in further work, the new approach could become a reliable diagnostic tool for people deemed at high risk for Parkinson’s because of family history or for those with confusing, vague, or nonspecific symptoms.
Parkinson’s disease, together with multiple-system atrophy (MSA) and dementia with Lewy bodies, two disorders with similarly dismal outcomes, belongs to a group of neurologic disorders that have in common the pathological aggregation of the ⍺-synuclein protein into toxic fibrils. Those fibrils disrupt multiple neurologic functions and ultimately cause neurons to die.
The symptoms displayed by patients with ⍺-synucleinopathies strongly overlap, which makes it hard to distinguish disorders early on and start patients on specifically tailored treatments.
None of the available therapies treat the causes of the diseases. Instead, they temporarily suppress symptoms.
For this work, Walt’s team collaborated with the lab of Vikram Khurana, HMS associate professor of neurology at Brigham and Women’s, which provided samples from people with Parkinson’s and MSA. The laboratory of physicist David Weitz at the Wyss Institute and the Harvard John A. Paulson School of Engineering and Applied Sciences, through the vital contributions of co-author and HMS graduate student Rohan Thakur, added expertise for the encapsulation of single ⍺-synuclein fibrils.
The researchers engineered so-called digital seed amplification assays, digital SAAs, to detect and count single ⍺-synuclein fibrils in samples of brain tissue and spinal fluid.
The researchers developed different diagnostic assays to detect ⍺-synuclein fibrils in patient samples. In the digital SAAs, individual fibrils are separated into different types of engineered microcompartments, and then, as seeds, grown into larger fluorescent aggregates that become easily detectable and countable.
“Our digital SAAs present a critical technological advance with the potential to turn pathological ⍺-synuclein into an early biomarker for this class of neurodegenerative diseases,” said co-first author Tal Gilboa, a postdoctoral research fellow in the Walt lab.
But work remains to be done, she cautioned.
“Our current strategies worked well on brain tissue samples from Parkinson’s disease 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 ⍺-synuclein fibrils in blood and other biological fluids.”
In addition to continuing to optimize the assays for diagnostic applications that could, in the future, distinguish between different ⍺-synuclein fibril structures forming in patients diagnosed with Parkinson’s disease, MSA, or dementia with Lewy bodies, Walt’s team is also exploring the platform’s potential for drug screening. The researchers showed that the potential of a small molecule to inhibit ⍺-synuclein aggregation can be accurately quantified using digital SAA and that the assay can read out different fibril morphologies.
“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 that enable or stimulate ⍺-synuclein aggregation in the body,” said co-first author Zoe Swank, HMS research fellow in pathology in the Walt lab. “Using this system flexibly could help us better understand how we can constrain aggregate growth.”
Authorship, funding, disclosures
Additional authors include Russell A. Gould, Kean Hean Ooi, Maia Norman, Elizabeth A. Flynn, Brendan T. Deveney, Anqi Chen, Ella Borberg, Anastasia Kuzkina, and Alain Ndayisaba.
This research was supported by a grant from the Michael J. Fox Foundation (grant number 2021A011886). Tal Gilboa is an awardee of the Weizmann Institute of Science Women's Postdoctoral Career Development Award.
Walt is a founder and equity holder in Quanterix.
