Home Cellular science Lab-grown ‘mini brains’ suggest treatments for neurodegenerative diseases

Lab-grown ‘mini brains’ suggest treatments for neurodegenerative diseases

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A common form of motor neuron disease, amyotrophic lateral sclerosis, often overlaps with frontotemporal dementia (ALS / FTD) and can affect younger people, occurring mainly after the age of 40-45 years. These conditions cause devastating symptoms of muscle weakness with changes in memory, behavior, and personality. Being able to develop small organ-like brain models (organoids) allows researchers to understand what happens in the early stages of ALS / FTD, long before symptoms start to appear, and to look for potential drugs. .

In general, organoids, often referred to as “mini-organs”, are increasingly used to model human biology and disease. At the University of Cambridge alone, researchers are using them to repair damaged livers, to study SARS-CoV-2 infection of the lungs and model the early stages of pregnancy, among many other areas of research.

Typically, researchers take cells from a patient’s skin and reprogram the cells to their stem cell stage – a very early stage of development at which they have the potential to develop into most cell types. These can then be grown in 3D clusters that mimic particular elements of an organ. Since many diseases are caused in part by defects in our DNA, this technique allows researchers to see how cellular changes – often associated with these genetic mutations – lead to disease.

Scientists at the John van Geest Center for Brain Repair, University of Cambridge used stem cells derived from patients with ALS / FTD to grow brain organoids that are about the size of a pea. These resemble parts of the human cerebral cortex in terms of embryonic and fetal development milestones, 3D architecture, cell type diversity, and cell-cell interactions.

While this is not the first time that scientists have developed mini brains from patients with neurodegenerative diseases, most efforts have only been able to develop them for a relatively short period of time, representing a limited spectrum of disorders. related to dementia. In results published today in Nature Neuroscience, the Cambridge team reports the growth of these models for 240 days from stem cells harboring the most common genetic mutation in ALS / FTD, which was not possible. previously – and in unpublished work, the team cultivated them for 340 days.

Dr András Lakatos, senior author who led research at Cambridge’s Department of Clinical Neuroscience, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and the way these cells interact at different times. as diseases progress.

“To get closer to this complexity, we need models that last longer and mimic the makeup of human brain cell populations in which disturbances typically occur, and that’s what our approach offers. Not only can we see what can happen early in the disease – long before a patient experiences symptoms – but we can also begin to see how the disturbances change over time in each cell. “

While organoids are typically grown in the form of cell balls, the first author, Dr. Kornélia Szebényi, generated organoid slice cultures derived from patient cells in Dr. Lakatos’ laboratory. This technique allowed most of the cells in the model to receive the nutrients needed to keep them alive.

Dr Szebényi said: “When cells are clustered into larger spheres, cells in the nucleus may not receive sufficient nutrition, which may explain why previous attempts to grow long-term organoids from cells of the patients were difficult. “

Using this approach, Dr Szebényi and his colleagues observed changes occurring in organoid cells at a very early stage, including cellular stress, DNA damage, and changes in the way DNA is transcribed into proteins. These changes affected nerve cells and other brain cells called astroglia, which orchestrate muscle movement and mental capacity.

“While these initial disruptions were subtle, we were surprised at how early changes occurred in our human model of SLA / FTD,” added Dr. Lakatos. “This study and other recent studies suggest that damage can start to accumulate as soon as we are born. We will need more research to understand if this is indeed the case, or if this process is advanced in the organoids by the artificial conditions in the dish.

In addition to being useful for understanding disease development, organoids can be a powerful tool for screening for potential drugs to determine which ones may prevent or slow disease progression. This is a crucial advantage of organoids, as animal models often do not show the typical changes associated with the disease, and it would be impossible to sample the human brain for this research.

The team showed that a drug, GSK2606414, was effective in relieving cellular problems common in ALS / FTD, including toxic protein buildup, cellular stress, and loss of nerve cells, thereby blocking one pathways that contribute to the disease. Similar drugs which are more suitable as drugs and approved for human use are now being tested in clinical trials for neurodegenerative diseases.

Senior collaborating author Dr Gabriel Balmus from UK Dementia Research Institute at Cambridge University said: Being able to identify other potential drug targets.

Dr Lakatos added, “We currently have no very effective options for treating ALS / FTD, and while there is a lot more work to be done after our discovery, it at least offers hope that it will. it may be possible in time to prevent or slow down. the disease process.

“It may also be possible in the future to be able to take skin cells from a patient, reprogram them to develop their ‘mini brain’ and test which unique combination of drugs is best for their disease.”

The study was primarily funded by the Medical Research Council UK, Wellcome Trust and Evelyn Trust.

Reference

Szebényi, K et al. Cultures of Human SLA / FTD Brain Organoid Slices Show Distinct Early Astrocytes and Targeted Neuronal Pathologies. Natural neuroscience; October 21, 2021; DOI: 10.1038 / s41593-021-00923-4


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