Rapid Parkinson's Model Opens Door to Personalized Treatments

Scientists at Brigham and Women’s Hospital, a key Mass General Brigham healthcare system member, have created a model that swiftly transforms stem cells into brain cells exhibiting protein structures associated with Parkinson’s disease (PD).

This advancement allows for investigating the disease's distinct and highly variable pathology in a laboratory setting. The research outlines the potential for this model to eventually facilitate the creation of personalized diagnostic and therapeutic approaches for Parkinson’s disease. The findings are reported in Neuron.

“We sought to assess how quickly we could make human brain cells in the lab that give us a window into key processes occurring in the brains of patients with Parkinson’s disease and related disorders like multiple system atrophy and Lewy body dementia,” states Vikram Khurana, MD, PhD, Chief of the Movement Disorders Division at BWH and Principal Investigator within the Ann Romney Center for Neurologic Diseases at BWH.

And, unlike previous models, we wanted to do this in a short enough timeframe for these models to be useful for high-throughput genetic and drug screens and easy enough for many labs to use across academia and industry.”

Vikram Khurana, Study Senior Author, Principal Investigator and Chief, Movement Disorders Division, Brigham and Women's Hospital

PD is a degenerative brain disease that progresses over time. Among other health issues, people with the disease frequently experience tremors, muscle stiffness, impaired speech, and slowed movement.

A build-up of proteins in neurons is a common feature of Parkinson's disease (PD) and other neurodegenerative diseases such as Alzheimer's disease. This misfolding of proteins results in impaired cell function. While some symptoms may be relieved by current PD therapies, the underlying cause of the protein misfolding is not addressed.

Current "Parkinson's in a dish" models are capable of successfully converting stem cells into brain cells, but they cannot do so quickly enough to allow for the study of cellular pathologies unique to each patient and the development of customized treatment plans.

This is crucial since there is variation among PD patients, and some patients may now benefit from a treatment plan that is tailored to their specific needs.

Using the technology developed by the Brigham research team, it is now possible to consistently convert stem cells into brain cells in weeks rather than months. Additionally, researchers can use this technology to create models that accurately represent the variety of protein misfolding pathologies that can arise in the brain during that time.

The problem is that the way protein clusters form in PD looks different in different patients, and even in different brain cells of the same patient. This begs the question: how do we model this complexity in the dish? And how do we do it fast enough for it to be practical for diagnostics and drug discovery?”

Vikram Khurana, Study Senior Author, Principal Investigator and Chief, Movement Disorders Division, Brigham and Women's Hospital

Khurana's lab developed this model by introducing transcription factors - specific cellular instructions that trigger the rapid differentiation of stem cells into distinct brain cell types - using unique delivery molecules known as PiggyBac vectors.

Subsequently, they exposed nerve cells to aggregation-prone proteins such as alpha-synuclein, which is essential for the development of protein clusters in Parkinson's disease and associated disorders.

By utilizing CRISPR/Cas9 and additional screening mechanisms, they detected various inclusion forms in the cells, some of which were beneficial and others which were harmful. Using their stem-cell models, they found similar inclusions in the real brains of deceased patients, demonstrating relevance to disease. The work opens up new possibilities for patient classification of protein pathologies and identification of potential target proteins for therapeutic interventions.

Although the model represents progress, researchers are working to resolve a few issues. It currently produces immature neurons to start. To simulate the effects of aging on the protein aggregates that form, the researchers plan to replicate this model using mature neurons.

Although the new system can quickly produce neurons and important inflammatory "glial" cells in the brain, this paper only examines the cells separately. The researchers are currently merging these cells to examine the inflammatory reactions to the protein aggregation process, which may be crucial for the advancement of Parkinson's disease.

The study's two lead authors, both research fellows in BWH's Department of Neurology, offered their thoughts on the clinical applications the lab is currently working on.

In one key application, we are utilizing this technology to identify candidate radiotracer molecules to help us visualize alpha-synuclein aggregation pathologies in the brains of living patients we see in the clinic.”

Alain Ndayisaba MD, Co-First Author, Brigham and Women's Hospital

“This technology will pave the way for rapidly developing ‘personalized stem cell models’ from individual patients. These models are already being used to efficiently test new diagnostic and treatment strategies ‘in a dish’ before jumping into clinical trials so we target the right drug to the right patient,” says Isabel Lam PhD, Study Co-First Author, Brigham and Women's Hospital.