Summary: Researchers have developed a model that rapidly converts stem cells into brain cells with Parkinson’s disease (PD) protein structures, enabling personalized study and treatment. This new approach can transform stem cells into brain cells within weeks, facilitating high-throughput genetic screening and drug screening.
By mimicking the different protein misfoldings observed in Parkinson’s disease patients, this model offers a practical tool for diagnosis and drug discovery. This advance could lead to personalized therapies for Parkinson’s disease and related neurodegenerative diseases.
Highlights:
- New model converts stem cells into Parkinson’s brain cells in weeks, not months.
- The model reflects various protein misfoldings, facilitating personalized treatment.
- This approach enables high-throughput genetic and drug screening for PD.
Source: Brigham and Women’s Hospital
Researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham Health System, have developed a model that rapidly converts stem cells into brain cells with protein structures characteristic of Parkinson’s disease (PD), enabling the study of the disease’s unique and highly variable pathology in a petri dish.
The study details how the model could one day be used to develop personalized diagnostic and treatment methods for Parkinson’s disease.
The results are published in Neuron.
“We sought to assess how quickly we could generate human brain cells in the laboratory that would give us insight into key processes occurring in the brains of patients with Parkinson’s disease and related disorders such as multiple system atrophy and dementia with Lewy bodies,” said lead author Vikram Khurana, MD, PhD, chief of the Division of Movement Disorders at BWH and principal investigator in the Ann Romney Center for Neurological Diseases at BWH.
“And, unlike previous models, we wanted to do this in a time frame that was short enough that these models would be useful for high-throughput genetic and drug screenings and easy enough to use for many labs in academia and industry.”
PD is a progressive, degenerative brain disease. People with the disease often experience motor slowdowns, tremors, muscle stiffness, and speech problems, among other health complications.
Parkinson’s disease, like other neurodegenerative diseases such as Alzheimer’s disease, causes proteins to build up in neurons, leading to protein misfolding and impaired cell function. Current therapies for Parkinson’s disease can alleviate some symptoms, but do not address the root cause of protein misfolding.
Existing “dish” Parkinson’s models can efficiently transform stem cells into brain cells, but not in a reasonable time frame to study patient-specific cellular pathologies to guide tailored treatment strategies.
“This is important because Parkinson’s patients are diverse and a single treatment strategy may now work for some patients.
“The Brigham research team’s technology not only allows the transformation of stem cells into brain cells to occur reproducibly in weeks instead of months, but also allows researchers to develop models that reflect the various protein misfolding pathologies that can arise in the brain during this time period.
“The problem is that the way protein clusters form in Parkinson’s disease differs across patients, and even across different brain cells within the same patient,” Khurana says. “That raises the question: How do we model this complexity in the petri dish? And how do we do it quickly enough that it’s practical for diagnostics and drug discovery?”
To create this model, Khurana’s lab used special delivery molecules called PiggyBac vectors to introduce specific cellular instructions, called transcription factors, to rapidly transform the stem cells into different types of brain cells.
They then introduced into the nerve cells proteins that are prone to aggregation, such as alpha-synuclein, which plays a central role in protein cluster formation in Parkinson’s disease and related disorders. Using CRISPR/Cas9 and other screening systems, they identified different types of inclusions forming in the cells, some protective and others toxic.
To demonstrate the relevance of this research to disease, they used their stem cell models to discover similar inclusions in real brains of deceased patients. This work allows for new approaches to classify protein pathologies in patients and determine which of these pathologies could be the best therapeutic targets.
Although this model is a step forward, it has several limitations that the researchers want to address. For one, it currently generates immature neurons. The researchers want to reproduce this model with mature neurons to model the effects of aging on the protein aggregates that form.
Although the new system can rapidly create key inflammatory neurons and glial cells in the brain, the current study only looked at these cells individually. The team is now combining these cells to study inflammatory responses to the protein aggregation process that could be important for Parkinson’s disease progression.
The two lead authors of the study, both researchers at the Department of Neurology at BWH, commented on the clinical applications already underway in the laboratory.
“In a key application, we are using 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,” said co-first author Alain Ndayisaba, MD.
“This technology will pave the way for the rapid development of ‘personalized stem cell models’ from individual patients. These models are already being used to efficiently test new diagnostic and treatment strategies ‘in the lab’ before moving to clinical trials, in order to target the right drug for the right patient,” said Isabel Lam, Ph.D., co-first author.
Paternity: In addition to Vikram Khurana, Isabel Lam and Alain Ndayisaba, BWH authors include Anastasia Kuzkina, Ricardo L. Sanz, Aazam Vahdatshoar, Arati Tripathi, Nagendran Ramalingam, Charlotte Oettgen-Suazo, Manel Boussouf, Timothy D. Martin, Max Schäbinger, Erin Schäbinger , Amrita Verma, Xiao Yu, Kelly Hyles, Chansaem Park, Xinyuan Wang, Stephen J. Elledge and Ulf Dettmer. Other authors include Amanda J. Lewis, YuHong Fu, Giselle T. Sagredo, Ludovica Zaccagnini, Meral Celikag, Jackson Sandoe, Nader Morshed, Toru Ichihashi, Theresa Bartels, Xin Jiang, Challana Tea, Zichen Wang, Hiroyuki Hakozaki, Thorold W. Theunissen. , Haoyi Wang, Rudolf Jaenisch, Susan Lindquist, Beth Stevens, Nadia Stefanova, Gregor Wenning, Wilma DJ van de Berg, Kelvin C. Luk, Rosario Sanchez-Pernaute, Juan Carlos Gómez-Esteban, Daniel Felsky, Yasujiro Kiyota, Nidhi Sahni. , S. Stephen Yi, Chee-Yeun Chung, Henning Stahlberg, Isidro Ferrer, Johannes Schöneberg, Glenda M. Halliday and Tim Bartels.
Disclosures:Khurana is a co-founder and senior advisor to DaCapo Brainscience and Yumanity Therapeutics, companies focused on central nervous system diseases. Chung and Jiang contributed to this work as employees of Yumanity Therapeutics. Ichihashi and Kiyota contributed to this work as employees of Nikon Corporation. Lam, Ndayisaba, Sandoe, and Khurana are inventors on a patent application filed by Brigham and Women’s Hospital regarding iPSC embryonic stem cell induced inclusion models.
Funding: National Institutes of Health (NIH), Aligning Science Across Parkinson’s (ASAP), Michael J. Fox Foundation, New York Stem Cell Foundation, Multiple System Atrophy Coalition, and private donors.
About this news on Parkinson’s disease and stem cell research
Author: Serena Bronda
Source: Brigham and Women’s Hospital
Contact: Serena Bronda – Brigham and Women’s Hospital
Picture: Image credited to Neuroscience News
Original research: The results will be presented in Neuron