Faster ‘in a dish’ model may speed up treatment for Parkinson’s

Researchers at Harvard-affiliated Brigham and Women’s Hospital have developed a new model using stem cells to rapidly create Parkinson’s disease in a petri dish, promising personalized diagnostic and treatment methods. The study’s results, published in Neuron, reveal that while existing models can transform stem cells into brain cells, they are too slow to study patient-specific cellular pathologies for tailored treatments. Given the diverse nature of Parkinson’s disease, a one-size-fits-all approach may not be effective. The new technology from Brigham's team enables a reproducible transformation from stem cells to brain cells within weeks instead of months, reflecting the varied protein misfolding pathologies seen in patients. Senior author Vikram Khurana, chief of the Movement Disorders Division at BWH, explained that their goal was to quickly create human brain cells in the lab to study processes occurring in Parkinson’s patients and related disorders like multiple system atrophy and Lewy body dementia. This new model is designed for high-throughput genetic and drug screens and is user-friendly for various labs. Parkinson’s disease is a progressive, degenerative brain condition causing symptoms such as slowed movement, tremors, muscle stiffness, and speech impairment. It leads to protein build-up in neurons, causing protein misfolding and impaired cell function. Current therapies only alleviate symptoms without addressing the root cause of protein misfolding. Khurana noted the challenge of modeling the different ways protein clusters form in PD in various patients and brain cells. To address this, his lab used PiggyBac vectors to deliver transcription factors that transform stem cells into different brain cells quickly. They then introduced aggregation-prone proteins like alpha-synuclein into nerve cells and used CRISPR/Cas9 and other systems to identify diverse protein inclusions, some protective and some toxic. These models helped discover similar inclusions in the brains of deceased patients, offering new ways to classify protein pathologies and identify potential drug targets. Despite this progress, the model has limitations. It currently generates immature neurons, and researchers aim to replicate the model with mature neurons to study aging effects on protein aggregates. Additionally, while the new system can create both neurons and key inflammatory glial cells, the current study examines these cells individually. The team is now combining these cells to study inflammatory responses to protein aggregation, important for PD progression. The study’s lead authors, research fellows in BWH’s Department of Neurology, highlighted ongoing clinical applications. Alain Ndayisaba noted they are using the technology to identify radiotracer molecules to visualize alpha-synuclein aggregation in patients' brains. Isabel Lam added that the technology allows for the rapid development of personalized stem cell models to test diagnostic and treatment strategies in the lab before clinical trials, ensuring targeted therapies for patients.