New Study of the Brain’s Circuitry Will Track Parkinson’s Disease From Its Origins

November 3, 2021

Berkeley neuroscientist Yang Dan will help conduct an ambitious $9 million project exploring how the circuitry in the brain progressively goes awry in patients suffering from Parkinson’s disease.

Dan brings her expertise as an acclaimed sleep scientist to an international team of investigators recently awarded the funding over the next three years by the Aligning Science Across Parkinson’s (ASAP) initiative. Launched in 2019, the research funding initiative aims to speed scientific discovery and illuminate the path to a cure for the debilitating neurodegenerative disorder.

Afflicting more than 1 million people in the United States alone, Parkinson’s produces symptoms ranging from tremors, slowness, and stiffness to cognitive difficulties and depression.

“In Parkinson’s, what we hear about is motor deficits, but it turns out Parkinson’s patients also have a ton of sleep problems,” says Dan, who holds Berkeley’s Nan Fung Life Sciences Chancellor’s Chair in Neuroscience. These problems include insomnia, fragmented sleep, and daytime sleepiness. Along with severely impairing patients’ quality of life, disrupted sleep may actually accelerate the progression of the disease.

Parkinson’s develops when brain cells that make dopamine, a neurotransmitter important to coordinating movement, stop working or die. The disease has no cure, and the drugs used to treat symptoms lose their effectiveness as the disease slowly advances.

Little is known about how the disease evolves. But scientists believe the dysfunction in the brain’s circuit mechanisms may start decades before patients ever display outward symptoms.

Understanding this “prodromal” or initial stage of the disease could lead to earlier diagnoses, better treatment of symptoms, and even the development of disease-modifying therapies.

Headed by D. James Surmeier, professor and chair of the Department of Neuroscience at Northwestern University, the study will unite a multidisciplinary team of scientists from research institutions across the United States and in Switzerland.

Surmeier recently developed a genetically engineered line of mice that mirror the slow, progressive development of Parkinson’s, including sleep disruptions, that is seen in humans. Previously, scientists only had access to mouse models that demonstrated symptoms of the disease in its latest stages.

“Understanding how the brain circuitry begins to dysfunction, begins to stop working properly is critical to us being able to identify people who’ve got the disease and will manifest five years, 10 years later,” Surmeier says. Catching and treating the disease early could make existing interventions work better or even lead to new strategies.

Color photo of Prof. Dan smiling slightly at the camera.
Professor Dan

While Dan will focus on how circuit problems impact sleep, the project’s other investigators will study how the dysfunction affects movement.

Dan recently made a surprising discovery linking those two impairments when she found that neurons controlling both sleep and movement share a common hub in the brain.

In a study published last year in the journal Science, Dan and her colleagues identified a population of neurons involved in sleep in the substantia nigra pars reticulata (SNr) — a basal ganglia structure in the midbrain where nerve cells responsible for movement also are located. The SNr receives input from the substantia nigra pars compacta (SNc), which contains dopaminergic neurons that are responsible for the production and secretion of dopamine. When these dopaminergic neurons are lost, the activity of SNr neurons is likely to become abnormal.

“Parkinson’s is very much believed to be a basal ganglia disease,” says Dan. “We sort of stumbled upon this motor-related region and we found that some of the neurons actually are very important for promoting sleep.”

Dan brings a fresh perspective to the ASAP project: She has not previously studied Parkinson’s disease.

One of the initiative’s goals is to spark new thinking by supporting the work of researchers from diverse backgrounds. “They actually wanted to attract people who don’t traditionally study Parkinson’s disease to start studying this,” says Dan, who also is a Howard Hughes Medical Institute investigator. “I would sort of fit the bill.”

Dan jumped at the chance to participate. She hopes to translate her work in basic science into better understanding and potential therapies for sleep problems plaguing Parkinson’s patients.

“We do think the SNr abnormality probably plays a huge role in the sleep deficit in Parkinson’s disease,” Dan says. “If we can figure out which part of the circuit malfunctions in this Parkinsonian mouse model then hopefully that can help to figure out why human Parkinson’s patients have sleep problems and hopefully that can even guide some interventions that can improve sleep. Once you know the symptom at the neuronal level rather than just a behavioral level, that really gives you a much better idea of what intervention might work.”

Because poor sleep is also linked to a wide variety of adverse health outcomes, identifying the circuit dysfunction that disturbs sleep might even improve the course of the disease. “If we could improve the quality of sleep early,” Surmeier hypothesizes, “we may actually slow the progression to clinical Parkinsonism.”

Along with Dan’s knowledge of sleep disorders, she is an expert in harnessing cutting-edge techniques, including optics, electrophysiology, and optogenetics, to chart the brain’s complex circuitry.

“Yang brings a very important and novel perspective to this whole effort,” says Surmeier.

The grant is one of 14 awards totaling $132 million recently announced by ASAP. One of the initiative’s unique features is its emphasis on collaboration, says Randy Schekman, a Nobel laureate, Berkeley professor of molecular and cell biology, and ASAP’s scientific director.

“The reward structure in academic science favors the individual,” Schekman says. “That isn’t always the best model, I think, particularly for a really complicated problem like Parkinson’s, which may have many different origins and progresses in unpredictable ways.”

To that end, ASAP teams are encouraged to share their ideas, techniques, and early findings via an electronic network and regular meetings.

Berkeley is well-represented in the ASAP awards. In the initiative’s first round of funding last year, teams led by Berkeley professors Donald Rio and James Hurley were among 21 groups receiving grants totaling $161 million.