Under normal conditions, tau protein is a crucial component of the brain's infrastructure, helping to stabilise neurons into their appropriate forms. Tauopathies, a type of brain illness, can be caused by difficulties with learning, memory, and movement, but tau can become tangled and toxic. The most prevalent tauopathy is Alzheimer's disease, although the group also includes Parkinson's disease, chronic traumatic encephalopathy, and numerous rare hereditary diseases.
In search of ways to prevent these ruthless tau tangles, scientists at the Washington University School of Medicine in St. Louis have identified a crucial step in their development. Intervening at this step could potentially forestall the catastrophic cascade of events that results in brain damage, the researchers said. The findings are published in the Molecular Psychiatry journal Sept. 20.
First author Reshma Bhagat, PhD, a postdoctoral researcher, came up with the idea of looking for such factors among a group of RNA molecules known as long noncoding RNAs that are not translated into proteins. RNA has not been considered a active element in biological processes, and most disease research has not focused on it. Only in the past decade have scientists discovered that these RNA molecules can play crucial roles in disease processes. Bhagat became attracted to lncRNAs because they are involved in regulating diverse cellular processes and have been linked to cancers.
The researchers began by examining skin cells from three individuals with a genetic tauopathies, each carrying a different mutation in the tau gene. The scientists converted the skin cells into brain neurons that carry each of the three mutations. The researchers utilized a molecular technique known as CRISPR to correct some of the skin cell mutations before converting them into neurons. They were able to obtain human brain cells with and without tau mutations, which didn't require human brain tissue.
The scientists identified 15 lncRNAs with tau mutations that were significantly increased or decreased in brain cells with tau mutations compared to their genetically matched controls. One lncRNA, SNHG8, which was low not only in the three human brain cells with tau mutations but also in mice with a tau mutation and in brain samples from people who had died of any of three different tauopathies: Alzheimer's disease, frontotemporal lobar degeneration with tau pathology, or progressive supranuclear palsy. The levels of SNHG8 in tauopathies, regardless of mutation, species or disease, were down in tauopathies, all signs that point to its role in a common pathological process.
The investigators further discovered that neurons with low SNHG8 levels had high levels of stress granules, RNA-protein complexes that form to help cells survive stress-related situations like excessive heat or low oxygen and disintegrate once the threat passes. The danger is in stress granules, which are rich in tau. If too many stress granules form or if they contain mutated tau particularly prone to tangling - as is the case in genetic tauopathies - stress granules can kickstart the aggregation process by concentrating tau.
Bhagat said, "It has been a difficult time for our people, and we have to learn how to take care of our children, he said.
Bhagat went back to the human neurons with tau mutations, the ones she developed out of skin cells from tauopathy patients. The cells had a high level of stress granules and persistent low levels of SNHG8. By replacing the SNHG8, she was able to bring down stress granules in such cells.
Bhagat, Karch and colleagues are working on identifying compounds that can shore up SNHG8 levels and looking at the effects of such compounds in animal models of tau aggregation and tauopathy.