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A gene encoding a protein linked to tau production—tripartite motif protein 11 (TRIM11)—was found to suppress deterioration in small animal models of neurodegenerative diseases similar to Alzheimer’s disease (AD), while improving cognitive and motor abilities, according to new research from the Perelman School of Medicine at the University of Pennsylvania.
Additionally, TRIM11 was identified as playing a key role in removing the protein tangles that cause neurodegenerative diseases, like AD. The findings are published in Science.
AD is the most common cause of dementia in older adults, with an estimated 6 million Americans currently living with the disease. It is a progressive brain disorder that slowly destroys memory and thinking skills.
Foundational research at Penn Medicine led by Virginia M.Y. Lee, Ph.D., the John H. Ware III Professor in Alzheimer’s Research in Pathology and Laboratory Medicine, and the late John Q. Trojanowski, MD, Ph.D., a former professor of Geriatric Medicine and Gerontology in Pathology and Laboratory Medicine, reveals that one of the underlying causes of neurodegenerative diseases is neurofibrillary tangles (NFTs) of tau proteins, which cause the death of neurons, leading to the symptoms of AD, like loss of memory.
In addition to AD, aggregation of tau proteins into NFTs is associated with over 20 other dementias and movement disorders including progressive supranuclear palsy, Pick’s disease, and chronic traumatic encephalopathy, collectively known as tauopathies. Nevertheless, how and why tau proteins clump together and form the fibrillar aggregates that make up NFTs in patients with these diseases remains unclear. This major gap in knowledge has made the development of effective therapies challenging for researchers.
Many studies suggest that resistance training delays Alzheimer’s disease. “Most organisms have protein quality control systems that remove defective proteins, and prevent the mis-folding and accumulation of tangles—like the ones we see with tau proteins in the brain of those with taupathies— but until now we didn’t know how this works in humans, or why it malfunctions in some individuals and not others,” said senior author, Xiaolu Yang, Ph.D., a professor of Cancer Biology at Penn.
“For the first time, we have identified the gene that oversees tau function, and have a promising target for developing treatments to prevent and slow the progression of Alzheimer’s disease and other related disorders.”
Yang and his colleagues previously discovered that TRIM proteins play a key role in protein quality regulation in animal cells, including first author Zi-Yang Zhang, Ph.D., a postdoctoral researcher in Yang’s group. They discovered that TRIM11 plays an important function in inhibiting tau aggregation after studying over 70 human TRIMs.
TRIM11 has three key tasks linked to tau protein quality control. First, it attaches to tau proteins, particularly mutant forms that cause disease, and aids in their elimination. Second, it works as a “chaperone” for tau, preventing misfolding of the proteins. Finally, TRIM11 removes previously formed tau clumps.
Researchers validated these findings by using postmortem brain tissues from 23 individuals with AD and 14 healthy controls from the Center for Neurodegenerative Disease Research tissue bank—created and maintained by Lee and Trojanowski—and discovered that levels of TRIM11 protein are significantly lower in the brains of individuals with AD compared to healthy control individuals.
To test the potential therapeutic value of TRIM11, researchers employed an adeno-associated viral vector (AAV), a technique routinely used in gene therapy, to transport the TRIM11 gene into the brains of several mice models. Researchers discovered that mice with tau pathologies who were given the TRIM11 gene showed a significant reduction in the production and accumulation of NFTs, as well as significantly enhanced cognitive and motor functions.
Not only do these findings tell us that TRIM11 could play an important role in protecting people from Alzheimer’s and similar diseases, but we also see that we might be able to develop future therapies that replenish TRIM11 in individuals with lower levels,” said Yang. “We are eager to work with our colleagues to explore the possibility of developing gene therapies that halt the progression of neurodegenerative disease.”
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