Breakthrough Discovery: RNA Molecule Unlocks Clues to Alzheimer’s Disease

Scientists Discover Key Step in Alzheimer’s Disease – Could Lead to New Treatments

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.

“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.

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 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.

Further investigation revealed that neurons with low SNHG8 levels also had high levels of stress granules, RNA-protein complexes that form to help cells survive stressful situations such as excessive heat or low oxygen and disintegrate once the threat passes. Stress granules are rich in tau, and therein lies the danger. If too many stress granules form or if they contain mutated tau particularly prone to tangling, stress granules can kickstart the aggregation process by concentrating tau.

Bhagat went back to the human neurons with tau mutations, the ones she had developed out of skin cells from tauopathy patients. These cells exhibited persistently low levels of SNHG8 and high levels of stress granules. By replacing the missing SNHG8, she was able to bring down the levels of stress granules in such cells.

“That’s really the killer experiment,” Karch said. “That shows that lncRNAs are impacting stress granule formation and that this pathway can be targeted to treat, potentially, a variety of tauopathies.”

Scientists at Washington University School of Medicine in St. Louis have discovered a critical step in the development of Alzheimer’s disease. Tau protein, normally essential for stabilizing neurons in the brain, can become toxic and form tangles that damage brain tissue. These tangles are a hallmark of Alzheimer’s and other neurodegenerative diseases. The researchers found that a group of RNA molecules known as long noncoding RNAs (lncRNAs) play a key role in the formation of tau tangles. One lncRNA in particular, called SNHG8, was consistently low in the brains of individuals with tauopathies, regardless of the specific genetic mutation causing the disease. SNHG8 appears to regulate the formation of stress granules, which are RNA-protein complexes that can trigger tau aggregation. When SNHG8 levels were restored in brain cells with tau mutations, the levels of stress granules decreased. This discovery opens up new avenues for potential treatments for Alzheimer’s and related diseases by targeting the SNHG8 pathway to prevent tau tangle formation.

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