Researchers have created an innovative model that swiftly transforms stem cells into brain cells exhibiting protein characteristics associated with Parkinson’s disease (PD). This advancement allows for the exploration of the disease’s distinct and variable pathology in laboratory settings.
At Brigham and Women’s Hospital, which is part of the Mass General Brigham healthcare system, a team has successfully developed a model capable of quickly converting stem cells into brain cells showing protein features linked to Parkinson’s disease (PD). This breakthrough facilitates the examination of the unique and variable pathology of the disease in controlled laboratory conditions. The study illustrates the potential of this model for future personalized diagnostic and treatment approaches for Parkinson’s disease. The findings are published in Neuron.
According to Vikram Khurana, MD, PhD, senior author and head of the Movement Disorders Division at BWH, “We aimed to determine how fast we could create human brain cells in the lab that would provide insight into critical processes happening in the brains of patients with Parkinson’s disease and related disorders such as multiple system atrophy and Lewy body dementia. Unlike previous models, our goal was to accomplish this rapidly enough to enable useful high-throughput genetic and drug screening, making it accessible to a broad range of laboratories in academia and industry.”
Parkinson’s disease is a progressive neurodegenerative condition. People who have PD typically experience symptoms such as slow movement, tremors, muscle rigidity, and communication difficulties, along with other health challenges. This disease, along with other neurodegenerative disorders like Alzheimer’s, leads to the accumulation of proteins in neurons, which results in misfolding and dysfunction of cells. While current medications can alleviate some symptoms, they do not address the underlying problem of protein misfolding.
Current “Parkinson’s in a dish” models are capable of converting stem cells into brain cells, but they do not do so within a timeframe that allows for studying patient-specific cellular conditions, which can inform personalized treatment approaches. Given the diversity among Parkinson’s patients, a universal treatment method may not be effective for everyone. The research team at Brigham has developed a technology that allows for the production of brain cells from stem cells within weeks rather than months, facilitating the creation of models that represent the varied protein misfolding issues that may arise in the brain during that period.
“The challenge lies in the fact that the formation of protein clusters in PD varies between patients and even among different brain cells in the same patient,” Khurana stated. “This raises the question of how we can accurately model this complexity in the laboratory and do so in a timeframe suitable for diagnostic and drug discovery purposes.”
To create this model, Khurana’s team employed specialized delivery systems known as PiggyBac vectors to introduce certain instructions, known as transcription factors, that speed up the conversion of stem cells into various brain cell types. They then added proteins prone to aggregation, like alpha-synuclein, which plays a crucial role in the development of protein clusters in PD and similar conditions, into nerve cells. Employing CRISPR/Cas9 and other screening methodologies, they identified different types of inclusions forming in the cells, some of which were protective while others were toxic. To verify the relevance of their findings to the disease, they compared their stem-cell models with brain tissue from deceased patients, discovering similar inclusions. This research facilitates new methods for categorizing protein pathologies in patients and identifying potential drug targets.
While this model represents significant progress, it has several limitations that researchers seek to address. Currently, it predominantly produces immature neurons. The team plans to enhance the model by generating mature neurons to mimic the effects of aging on protein aggregates. Although the new approach can quickly produce both neurons and essential inflammatory “glial” cells, the current study focuses solely on these cell types individually. The researchers are now working on integrating these cells to investigate the inflammatory responses linked to protein aggregation, which may be vital to PD development.
The two primary authors of the study, who are both research fellows in the Department of Neurology at BWH, shared insights on clinical applications already being explored in the lab. “One major application involves using this technology to find candidate radiotracer molecules to visualize alpha-synuclein aggregation in the brains of living patients we see in the clinic,” stated co-first author Alain Ndayisaba, MD.
“This technology will enable the swift development of ‘personalized stem cell models’ for individual patients. These models can be utilized to effectively test new diagnostic and therapeutic strategies ‘in a dish’ before moving into clinical trials, ensuring that the appropriate drug is given to the right patient,” added co-first author Isabel Lam, PhD.
