Friday, 30 August 2013

Researchers use iPSCs technology to generate neurons in a dish, revealing new clues behind deadly brain diseases

Gladstone's Helen Fong & Yadong Huang
Currently, there is no easy or simple way to study diseases of the brain. Harvesting neurons from a living patient is both difficult and risky, while examining brain tissue post-mortem usually reveals information about the disease's final stages. On the other hand, animal models although incredibly informative, have frequently fallen short during the crucial drug-development stage of research. As a result, we are largely unable to treat this class of diseases.

Today, scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF) are taking a new approach: they use induced pluripotent stem cells (iPSCs) to create a human model of degenerative disease in a dish.

Using this model, the team uncovered a molecular process that causes neurons to degenerate, a hallmark sign of many conditions, including Alzheimer's disease and frontotemporal dementia (FTD). Their latest study, published in the latest issue of Stem Cell Reports, offers new hope in the continued battle against many neurodegenerative disorders.

"So much about the mechanisms that cause tauopathies is a mystery, in part because traditional approaches -- such as post-mortem brain analysis and animal models -- give an incomplete picture. But by using the latest stem-cell technology, we generated human neurons in a dish that exhibited the same pattern of cell degeneration and death that occurs inside a patient's brain. Studying these models allowed us to see for the first time how a specific genetic mutation may kick start the tauopathy process."  explained Dr. Huang. 

Other researchers recently discovered that the Tau mutation in question may have the capacity to increase a person's risk of developing different tauopathies, including Alzheimer's or FTD. So the UCSF researchers, in collaboration with Bruce Miller, MD, who directs the UCSF Memory and Aging Center and who provided skin cells from a patient with the Tau mutation, transformed these cells into iPSCs. The team then combined this method with a cutting-edge gene-editing technique that essentially eliminated the Tau mutation in some of the iPCs cells. This gave them a system which allowed the team to compare neurons that had the mutation to ones that didn't.

"Our approach allowed us to grow human neurons in a dish that contained the exact same mutation as the neurons in the brain of the patient. By comparing these diseased neurons with the 'genetically corrected' healthy neurons, we could see -- cell by cell -- how the Tau mutation leads to the abnormal build up of Tau and, over time, neuronal degeneration and death."  said first author Helen Fong, PhD, who is also a California Institute for Regenerative Medicine postdoctoral scholar. 

"Tau's main functions include keeping the skeletal structure of individual neurons intact and regulating neuronal activity. But our research showed that the Tau produced by neurons from people with the Tau mutation is different; so it is red-flagged by the cell and targeted for destruction. However, instead of being flushed out, Tau gets chopped into pieces. These potentially toxic fragments accumulate over time and may in fact cause the neuron to degenerate and die." said Dr. Huang. 

By correcting the Tau mutation, the research team effectively removed Tau's red flag. The protein remained in one piece, the abnormal buildup ceased and the neurons remained healthy. Ongoing studies aim to determine whether the abnormal fragmentation and buildup of mutant tau is really the main cause of the neuronal death and, if so, how to block it.

Finding a way to block this toxic buildup of tau fragments has been a key focus of drug development -- but has thus far been unsuccessful. However, Dr. Huang and his team stay optimistic, believing that their approach could be exactly what researchers need to fight against deadly tauopathies.

"These findings not only offer a glimpse into how these powerful new models can shed light on mechanisms of disease. They may also prove invaluable for screening potential drugs that could be developed into better treatments for Alzheimer's disease, FTD and related conditions." said Dr. Miller.

Helen Fong, Chengzhong Wang, Johanna Knoferle, David Walker, Maureen E. Balestra, Leslie M. Tong, Laura Leung, Karen L. Ring, William W. Seeley, Anna Karydas, Mihir A. Kshirsagar, Adam L. Boxer, Kenneth S. Kosik, Bruce L. Miller, Yadong Huang. (2013). Genetic Correction of Tauopathy Phenotypes in Neurons Derived from Human Induced Pluripotent Stem Cells. Stem Cell Reports DOI: 10.1016/j.stemcr.2013.08.001 

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