Scientists develop brains-in-a-dish to better study Parkinson’s disease 

By Drima Chakraborty, Trainee

Small pea-sized human midbrain-like organoids

Scientists have—for the first time—grown mini-brains that mimic the major pathological features of Parkinson’s disease from human stem cells. The scientists, who come from A*STAR’s Genome Institute of Singapore (GIS), the National Neuroscience Institute (NNI), and Duke-NUS Medical School,  published their findings in the Annals of Neurology in September 2021.

Parkinson’s disease, characterised by its impact on muscle control, affects three in every 1,000 Singaporeans aged 50 and older. Worldwide, it is the fastest growing and second most common age-related progressive neurodegenerative disorder. A main feature of Parkinson’s disease is the selective loss of the midbrain dopaminergic neurons (mDA) in the part of the brain known as the pars compacta, leading to a dopamine deficit and motor and cognitive issues.

And so far, scientists have not been able to uncover an effective therapy for the condition. This is partially because prior research relied on data from animal models, which have been unable to reproduce the hallmark pathological features seen in human patients.

“Recreating models of Parkinson’s disease in animal models is hard as these do not show the progressive and selective loss of neurons that produce the neurotransmitter dopamine, a major feature of Parkinson’s disease,” said Professor Ng Huck Hui, a senior group leader at GIS, who is a senior co-author of the study. “Another limitation is that experimental mouse models of Parkinson’s disease do not develop characteristic clumps of proteins called Lewy bodies, which are often seen in the brain cells of people with Parkinson’s disease and a type of progressive dementia known as Lewy body dementia.”

To overcome this limitation, the team turned to organoids—rice grain-sized replicas of human midbrains—made from embryonic stem cells. They manipulated the DNA of these stem cells to include mutated versions of the glucocerebrosidase (GBA1) gene and α-synuclein (SNCA) gene, which are considered major risk factors for Parkinson’s disease. People with early-onset Parkinson’s disease who have a GBA1 gene mutation have been observed to form Lewy bodies at a higher rate than those without. With a GBA1 mutation, glucocerebrosidase is unable to break down the aggregated α-synuclein produced by the SNCA mutation. As the protein accumulates, it clumps together, forming Lewy bodies, a distinctive feature of Parkinson’s disease.

“These experiments are the first to recreate the distinctive features of Parkinson’s disease that we see only in human patients,” said Associate Professor Hyunsoo Shawn Je, a senior co-author from the Neuroscience and Behavioural Disorders Programme at Duke-NUS. “We have created a new model of the pathology involved, which will allow us to track how the disease develops and how it might be slowed down or stopped.”

With this new organoid model, the researchers showed, for the first time, that the loss of glucocerebrosidase and an over-expression of α-synuclein result in the formation of Lewy body-like clusters, a discovery that could finally be a step forward in the understanding of the underlying mechanisms of Parkinson’s disease.

“It’s a major challenge to extend healthy living years in an ageing global population, whose physical and cognitive performance often declines due to neurodegenerative disorders,” said Professor Tan Eng King, the deputy medical director responsible for academic affairs at NNI and  a senior co-author of the study. “This discovery provides insights and a ‘humanised’ disease model that can facilitate drug testing against Parkinson’s disease and dementia. Our organoid model with a genetic mutation on the GBA gene is also highly relevant as we have several of these genetic mutation carriers locally.”

The organoid system will enable research into Parkinson’s disease that is not possible with current animal models or the two-dimensional cultures of human mDA neurons. The team is currently in the process of using their organoids to further investigate how Lewy bodies form and understand how Lewy-body formation in dopamine-producing neurons results in neuronal loss. By studying these processes, they aim to find therapeutic targets that could slow the progression of Parkinson’s disease or even prevent the disease itself.

“The human organoid model is still in its infancy. Singapore has a lot of excellent stem cell biologists, geneticists, chemical engineers, mechanical engineers, material scientists, and medical doctors,” Je added. “We should collaborate to establish a nationwide, world-class research platform that can bridge the gap between our organoid models with human organs, and the gap between research finding and therapeutic translation. This is an unprecedented opportunity for Singapore to be a leader in this emerging field.”

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