April is Parkinson’s Disease Awareness month. Parkinson's disease (PD) is a neurodegenerative disorder of the nervous system and was originally described based on a set of motor symptoms, namely: tremor while at rest, slowness of movement, and increased muscle tone or rigidity. The signature pathological abnormality in PD is the formation of aggregates called Lewy bodies in nerve cells; though it is important to note that there are some people with PD without Lewy bodies. Lewy bodies contain a protein called synuclein and mutations that cause overproduction of synuclein can cause PD. Nerve cells that develop Lewy bodies in PD do not function properly and may die; most notably are those in the midbrain that make the neurotransmitter dopamine. Treatment with the drug levodopa, or L-dopa (the precursor to dopamine), can cause remarkable improvements in the motor symptoms of PD, particularly in the early stages of the disease. However, as the disease progresses, people living with PD may develop difficulty walking, talking, and swallowing, as well as fatigue, sleep disorders, and memory and cognitive problems called Parkinson’s disease dementia (PDD). In some people, Lewy bodies occur first in higher brain regions, causing trouble with attention, memory, and hallucinations, before the motor signs of PD develop. This disorder is termed Lewy body dementia (LBD). Signatures of Alzheimer’s disease also occur in a sizable proportion of people with LBD and PDD.
Some PD symptoms, such as loss of sense of smell, constipation, trouble maintaining normal blood pressure upon standing up, and certain sleep disturbances, can occur long before the classic motor symptoms of PD emerge. Recently, synuclein aggregates have been found in the spinal fluid and nerves supplying the skin, gut, and other organs in people with PD. The aggregates may occur years or decades before the motor symptoms of PD appear. These recent findings put a premium on understanding how to prevent PD in those at risk and slowing down progression in those already affected by PD.
There is no cure for PD, and currently available treatments like L-dopa and deep brain stimulation (DBS) lose their effectiveness as the disease progresses over time. Despite considerable public and private interest in developing therapeutics for PD, a gap remains between our understanding of the processes underlying PD and the development of therapies that target those processes in people living with PD. One recent and promising advance from PD research is a new way to detect the disorder early. Scientists have now developed a test called the alpha-synuclein seed amplification assay, which detects misfolded alpha synuclein protein in the fluid that surrounds the brain. This test still requires additional validation, but current data suggest that it shows good accuracy in diagnosing a specific form of PD. Even more promising is that it can do so years before motor symptoms begin, offering the exciting possibility of diagnosing and treating PD early enough to minimize or prevent the development of disabling symptoms.
This new assay for PD builds on a method for detecting misfolded proteins that was originally applied to prion disease and developed by the Rocky Mountain Laboratories, a component of the National Institute of Allergy and Infectious Diseases. Prions are proteins that form aggregates and their aggregation spreads throughout the brain. One compelling hypothesis is that synuclein aggregates can act like prion proteins and cause aggregation to spread in the nervous system as well. A major research effort focuses on preventing this spread of synuclein aggregates. The synuclein seeding assay test currently requires a spinal tap, but NINDS-supported scientists are working on applications of the assay that would be less invasive, such as those that would test blood, saliva, or skin. For instance, investigators funded through the NINDS Parkinson’s Disease Biomarkers Program (PDBP) are helping to develop a way to test for levels of alpha-synuclein aggregates in skin samples.
Through the PDBP and other programs, NINDS is supporting further efforts to identify biomarkers to aid in diagnosing PD and in research to understand disease processes and develop new treatments. NINDS has expanded the scope of PDBP to include diseases related to PD, like progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), and thanks to increased funding for Alzheimer’s disease and related dementias (AD/ADRD), we have brought LBDs, including PDD, into the program as well. In addition, NINDS is driving the discovery of new biomarkers for PD though the Accelerating Medicines Partnership® for PD (AMP PD) program. This public-private partnership is a collaboration between the NIH, FDA, non-profit organizations, and industry that conducts large-scale biomarker discovery using whole genome sequencing and gene and protein expression analyses (transcriptomics and proteomics) on a vast dataset from patient cohorts made available through a centralized web portal. Robust updates were released last November in AMP PD Version 4, which includes data from over ten thousand participants. Also, the AMP PD program has partnered with the Global Parkinson’s Genetics Program (GP2) to bring GP2’s genotyping data from 150,000+ international patients onto the AMP PD platform and provide a one-stop, cloud-based computing shop for Parkinson’s disease omics data.
Our end goal is to develop new treatments to slow, halt, or prevent PD. Research discoveries must move from lab settings into the clinic to have a real-world impact on the lives of those living with PD. For potential new therapies, the transition from lab-based research to industry-focused development can be a major challenge. NINDS supports translational research programs like the Blueprint Neurotherapeutics Network (BPN) for Small Molecules and BPN-Biologics, which bridge the typical endpoint of NIH-funded research and the beginning of industry drug development. In addition, on April 23-24, 2024, NINDS is hosting a hybrid workshop titled “Advances in Therapeutics Development for Parkinson’s Disease” to identify the gaps in our understanding about how to intervene in PD and to determine, as a community of academic, industry, non-profit, and people with lived experience, how to narrow those gaps. Registration for virtual attendance is free and open to the public. Visit the event website to register and find more information, including the detailed agenda and speaker list.
Finally, I am proud of the intramural basic, translational, and clinical research on PD conducted at NINDS and the cadre of NIH neuroscience research labs in the state-of-the-art John Edward Porter Neuroscience Research Center. Notably, three Porter Center investigators who have worked on unraveling the complexities of PD recently received the prestigious Life Sciences Breakthrough Prize: Ellen Sidransky (2024), Andrew Singleton (2024), and Richard Youle (2021). The Breakthrough Prize in Life Sciences honors transformative advances toward understanding living systems and extending human life.
As I reflect this April on the progress we have made in PD research and the challenges we have yet to overcome, I remain confident that our research community will continue to drive the discoveries that will offer hope to all those whose lives have been touched by PD.