Summary: An experimental drug related to diabetes medications slows Parkinson’s disease progression and reduces symptoms in mouse models, according to Johns Hopkins researchers.
Source: Johns Hopkins Medicine.
Johns Hopkins researchers report that an experimental compound, NLY01, which targets glucagon-like peptide-1 receptors similar to some diabetes drugs, slows the underlying progression of Parkinson’s disease and preserves motor function in mouse models. In laboratory studies using human brain cell cultures and live mice, the drug prevented the degeneration of neurons characteristic of Parkinson’s and blocked harmful cellular interactions that drive disease progression. Researchers anticipate moving NLY01 into clinical trials.
“It is amazingly protective of target nerve cells,” says Ted Dawson, M.D., Ph.D., director of the Institute for Cell Engineering and professor of neurology at Johns Hopkins University School of Medicine.
Dawson and colleagues suggest that if NLY01 proves safe and effective in people, it could be among the first therapies to directly slow Parkinson’s disease rather than only treating symptoms such as muscle rigidity, involuntary movements, fatigue, dizziness, and cognitive decline. Their full report appears in Nature Medicine, published June 11.
NLY01 is a long-acting agonist of the glucagon-like peptide-1 receptor (GLP1R), a target already exploited by several approved drugs for type 2 diabetes. Prior animal studies hinted that GLP1R agonists might protect the brain, but the exact cellular mechanism in Parkinson’s disease was unclear. The Johns Hopkins team investigated how NLY01 interacts with key brain cell types and how it influences the cellular cascade that leads to neuronal loss.
Using human-derived cells, researchers examined astrocytes, microglia and neurons. They found that microglia—the immune-like cells of the brain that respond to injury or infection—expressed the most GLP1R binding sites for NLY01. Expression was roughly twice as high in microglia compared with the other cell types and was markedly elevated in samples from people with Parkinson’s disease.
The team focused on a damaging interaction in the diseased brain: activated microglia release signals that convert supportive astrocytes into a reactive A1 phenotype. These A1 astrocytes become neurotoxic, attacking synapses and neuronal connections and accelerating cell death. In cell-culture experiments, treating microglia with NLY01 suppressed those activating signals. When treated microglia were combined with healthy astrocytes, the astrocytes did not convert into the destructive A1 form and instead retained their normal, neuroprotective functions.
To test whether this cellular protection translated to preserved brain function, the researchers evaluated NLY01 in two mouse models of Parkinson’s disease. In one model, mice received injections of alpha-synuclein fibrils—protein aggregates widely implicated in Parkinson’s pathology. Untreated mice developed progressive motor deficits over six months, as measured by behavioral tests such as the pole test. Mice treated with NLY01 retained normal motor performance and showed no loss of dopamine-producing neurons, indicating strong neuroprotection.
In a second model, transgenic mice that overproduce a human form of alpha-synuclein (a model of genetic Parkinson’s) normally develop fatal neurodegeneration within a predictable timeframe. Treatment with NLY01 extended survival in treated animals by more than 120 days and substantially reduced behavioral and neuropathological signs of disease. Examination of treated brains revealed far fewer features of Parkinson’s-related neurodegeneration.
Parkinson’s disease is a progressive neurodegenerative disorder that affects roughly one million people in the United States. Early signs can include tremor, sleep disturbances, constipation and slowed movement; later stages often bring greater motor impairment, speech difficulties and cognitive decline. Most diagnoses occur in older adults, though younger cases are documented.
Dawson notes that NLY01 still requires human safety and efficacy testing. However, because GLP1R agonists are already used clinically for diabetes and have established safety profiles, he expects fewer barriers to translation into clinical trials. NLY01 is designed for improved brain penetration and longer action compared with existing GLP1R drugs such as exenatide, liraglutide and others.
The study team includes researchers from Johns Hopkins University School of Medicine and collaborators from multiple institutions. Key contributors named in the report include Seung Pil Yun, Tae-In Kam, Nikhil Panicker, SangMin Kim, Seung-Hwan Kwon, Hyejin Park, Sangjune Kim, Nayeon Oh, Nayoung Alice Kim, Saebom Lee, Manoj Kumar, Daniel An, Sung-Ung Kang, Yumin Oh, Jong-Sung Park, Young Joo Park, Donghoon Kim, Zoltan Mari, Seulki Lee, Ted M. Dawson and Valina L. Dawson, among others. Additional collaborators represent institutions in the United States and the Republic of Korea and include scientists with expertise in neurology, molecular biology and translational research.
Funding: Research support was provided by the National Institute of Neurological Disorders and Stroke, the Maryland Stem Cell Research Foundation, the JPB Foundation, the National Institute on Aging, the American Parkinson Disease Association Research Grant Awards and the National Research Foundation of Korea.
The investigators demonstrate that NLY01, a brain-penetrant long-acting GLP1R agonist, prevents microglia-driven conversion of astrocytes into the neurotoxic A1 phenotype and thereby protects dopaminergic neurons in multiple Parkinson’s disease models. NLY01 reduced behavioral deficits, limited neuropathology, and extended survival in mouse models that mimic both sporadic and genetic forms of Parkinson’s disease. These findings identify a mechanism for GLP1R-mediated neuroprotection—blocking microglial signaling that induces A1 astrocytes—and support evaluation of NLY01 as a potential disease-modifying therapy for Parkinson’s and related disorders characterized by microglial activation.