Key Step in Tau Tangle Development Identified by Researchers

Wednesday - March 6 2024, 11:18 UTC - 11 months ago

Researchers have identified a key step in the development of destructive tau tangles, which are responsible for brain diseases known as tauopathies. By targeting this step and studying the role of long noncoding RNAs (lncRNAs), scientists hope to find new therapeutic approaches for these devastating conditions. One particular lncRNA, SNHG8, has been found to play a role in regulating tau protein aggregation and shows potential as a target for intervention.

Under normal circumstances, tau protein is part of the brain’s infrastructure, important for stabilizing neurons into their proper shapes. But sometimes tau gets knotted up into tangles and turns toxic, injuring brain tissue and causing tauopathies, a group of brain diseases characterized by problems with learning, memory, and movement. Alzheimer’s disease is the most common tauopathy, but the group also includes Parkinson’s disease, chronic traumatic encephalopathy (CTE), and several rare genetic conditions.

In search of ways to prevent these destructive tau tangles, researchers at Washington University School of Medicine in St. Louis have identified a key step in their development. Intervening at this step potentially could forestall the destructive cascade of events that results in brain damage, the researchers said. The findings were published on September 20 in the journal Molecular Psychiatry.

“Tauopathies are devastating diseases that have limited treatment options right now, and they all have this feature of tau aggregation,” said senior author Celeste Karch, PhD, a professor of psychiatry. “We’ve been thinking for a long time about whether there are factors that impact that common process of tau aggregation and if so, whether we could target those factors as a novel approach to treatment. These findings move us one step closer to finding a way to intervene and stop the process of tau aggregation that leads to dementia.” .

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 (lncRNAs) that are not translated into proteins. Historically, RNA has not been considered an active element in biological processes, and most disease research has not focused on them. Only in the past decade have scientists recognized that these RNA molecules can play critical roles in disease processes. Bhagat became interested in lncRNAs because they are involved in regulating diverse cellular processes and have been implicated in cancers.

To investigate the role of lncRNAs in tauopathies, the researchers started with skin cells from three people with a genetic tauopathy, each of whom carried a different mutation in the tau gene. Using molecular techniques, the researchers converted the skin cells into brain neurons that carry each of the three mutations. For comparison, they used a molecular technique known as CRISPR to correct the mutations in some of the skin cells before converting them into neurons. In this way, they were able to obtain human brain cells with and without tau mutations, which didn’t require using human brain tissue.

Using these cells, the researchers identified 15 lncRNAs that were significantly increased or decreased in brain cells with tau mutations compared to their genetically matched controls. One lncRNA, in particular, stood out: SNHG8, which was low not only in the three human brain cells with tau mutations but also in mice with a tau mutation. Further experiments showed that increasing the levels of SNHG8 in cells prevented the formation of tau tangles and reduced the toxicity caused by tau mutations.

These findings suggest that SNHG8 may play a role in regulating the aggregation of tau protein and could potentially be targeted for therapeutic interventions in tauopathies. The researchers also plan to investigate whether changes in SNHG8 levels are present in other neurodegenerative diseases and if targeting this lncRNA could have potential benefits in those conditions as well.

In summary, the identification of this key step in tau tangle development by researchers provides promising new insights into potential therapeutic approaches for tauopathies. By targeting factors such as lncRNAs, we may be able to prevent the damaging effects of tau tangles and improve outcomes for individuals affected by these devastating diseases.