In an enormous leap forward in the understanding of Parkinson’s disease (PD), researchers have discovered a new tool that can reveal a key pathology of the disease: abnormal alpha-synuclein — known as the “Parkinson’s protein” — in brain and body cells. The breakthrough, announced last night as it was published in the scientific journal The Lancet Neurology, opens a new chapter for research, with the promise of a future where every person living with Parkinson’s can expect improved care and treatments — and newly diagnosed individuals may never advance to full-blown symptoms.
The tool, called the α-synuclein seeding amplification assay (αSyn-SAA), can detect pathology in spinal fluid not only of people diagnosed with Parkinson’s, but also in individuals who have not yet been diagnosed or shown clinical symptoms of the disease, but are at a high risk of developing it.
The assay can confirm the presence of abnormal alpha-synuclein, detected in most people with PD, with astonishing accuracy: 93 percent of people with Parkinson’s who participated in the assay were proven to have abnormal alpha-synuclein. “We've never previously been able to see in a living person whether they have this alpha-synuclein biological change happening in their body,” says Todd Sherer, PhD, chief mission officer, The Michael J. Fox Foundation (MJFF).
The biomarker breakthrough was achieved by an international coalition of scientists led by MJFF and its landmark clinical study, Parkinson’s Progression Markers Initiative (PPMI). Its significance as a milestone in the pursuit of a cure and better treatments and therapies for Parkinson’s is highlighted in an article today on leading health and science news website STAT, which stated “The trophy is science — and specifically research funded by the Michael J. Fox Foundation for Parkinson’s Research that has resulted in the clearest evidence yet that the presence of a particular misfolded protein, alpha-synuclein, can be used to determine if people have Parkinson’s. It is an advance that may soon be used to develop better diagnostics, but more importantly could rapidly accelerate the search for treatments for the disease.” Read the article here.
A protein normally found in the nervous system, alpha-synuclein — like amyloid in Alzheimer’s disease — can start to misfold and clump, damaging neurons and causing Parkinson’s disease to develop. It has previously been possible to confirm the presence of these clumps only through postmortem analysis.
The new tool cleverly takes advantage of a telling characteristic of alpha-synuclein that is pathologic: it causes nearby, normal alpha-synuclein to also misfold and clump. For the assay, spinal fluid samples are prepared with a fluorescing agent that lights up if alpha-synuclein clumps form. Normal alpha-synuclein is then seeded into the spinal fluid sample. If abnormal alpha-synuclein is present in the sample, clumps form and the dye lights up. If no abnormal alpha-synuclein is present, the dye doesn’t fluoresce.
After being tested in small, independent studies, in 2022 the assay was validated in the large, well-characterized cohort of PPMI. The validation was carried out in some 1,123 samples of spinal fluid contributed by PPMI participants over the years. The assay proved amazingly accurate, with 93 percent of participants with Parkinson’s having an abnormal test. (Very few tests for neurologic disorders are over 90 percent sensitive for disease.) And, importantly, the test was abnormal in less than 5 percent of people without Parkinson’s.
Steady and critical advances in the pursuit of a reliable and accurate biomarker test have been the hallmark of PPMI, which was built for this purpose. The discovery enabled by the new test is the latest, and most significant, finding to date from the study.
Today, with this discovery in hand, Parkinson’s is moving from a disease primarily understood, diagnosed and measured through subjective clinical assessments to an objectively biologically defined disease — which makes possible new paradigms for clinical care, including earlier diagnosis and targeted treatments, and faster, smarter and cheaper drug development.
By helping to identify people at the earliest stages of PD, “We could then study what happens at different biological stages of the disease,” says Dr. Sherer. Says Ken Marek, MD, PPMI principal investigator, “αSyn-SAA enables us to move to another level in effecting new strategies for prevention of disease.”
The expansion of PPMI to increase volunteer recruitment efforts and remote testing for those at-risk for PD, as well as expanding efforts to enable breakthroughs such as αSyn-SAA, is supported by major funding from Aligning Science Across Parkinson’s (ASAP), a coordinated research initiative focused on accelerating the pace of discovery and informing the path to a cure for Parkinson’s. In addition to ASAP, PPMI is supported by the Edmond J. Safra Foundation, the Farmer Family Foundation, Connie and Steven Ballmer, and Susan and Riley Bechtel.
MJFF is urgently driving the next stages of development of αSyn-SAA toward widespread and standard use. Since today the tool can elicit a binary response — showing that abnormal synuclein is either present or not — there is tremendous promise in optimizing it, in order to measure the amount of alpha-synuclein present. Optimized assays would also detect abnormal synuclein through blood draw or nasal swab — a simple test that could be done in any doctor’s office.
“I’m moved, humbled and blown away by this breakthrough, which is already transforming research and care, with enormous opportunity to grow from here,” says Michael J. Fox. “I’m so grateful for the support of patients, families and researchers who are in it with us as we continue to kick down doors on the path to eradicating Parkinson’s once and for all.”
Read more of Michael J. Fox’s thoughts on the historic importance of the biomarker breakthrough and its implications for “biology’s century” in his opinion piece published today in STAT. Go to article.
Tune in Thursday, April 20, at 12 p.m. ET for a special edition of our Third Thursdays Webinar and learn more about the discovery of the biomarker and what it means for patients and their families. Register now.