According to new research from the Perelman School of Medicine at the University of Pennsylvania, a gene called tripartite motif protein 11 (TRIM11) has been found to suppress deterioration in small animal models of neurodegenerative diseases similar to Alzheimer’s disease (AD), while improving cognitive and motor abilities. Additionally, TRIM11 plays a key role in removing the protein tangles that cause neurodegenerative diseases like AD. These findings were published today in Science.
AD is the most common cause of dementia in older adults, with around 6 million Americans currently living with the disease. It is a progressive brain disorder that gradually destroys memory and thinking skills. Foundational research at Penn Medicine led by Virginia M.Y. Lee, PhD, and the late John Q. Trojanowski, MD, PhD, reveals that neurofibrillary tangles (NFTs) of tau proteins are one of the underlying causes of neurodegenerative diseases, leading to symptoms like memory loss.
Aggregation of tau proteins into NFTs is associated with over 20 other dementias and movement disorders. However, the mechanisms behind the clumping of tau proteins and the formation of NFTs in these diseases remain unclear. This knowledge gap has made it challenging for researchers to develop effective therapies.
“Most organisms have protein quality control systems that remove defective proteins and prevent the accumulation of tangles, like the ones we see in patients with taupathies. But until now, we didn’t understand how this works in humans or why it malfunctions in some individuals,” said senior author Xiaolu Yang, PhD. “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 team discovered that TRIM11 plays a crucial role in protein quality control and suppressing tau aggregation. It binds to tau proteins, especially the mutant variants that cause disease, helping to eliminate them. TRIM11 also acts as a “chaperone” for tau, preventing mis-folding, and dissolves pre-existing tau aggregates.
In a study using postmortem brain tissues from individuals with AD, researchers confirmed that the levels of TRIM11 protein are significantly reduced compared to healthy controls. They then used adeno-associated viral vector (AAV) to deliver the TRIM11 gene into the brains of multiple mouse models. The mice receiving the TRIM11 gene exhibited a decrease in the development and accumulation of NFTs and showed improved cognitive and motor abilities.
“These findings suggest that TRIM11 could play a crucial role in protecting against Alzheimer’s and similar diseases. We may also be able to develop therapies that replenish TRIM11 in individuals with lower levels,” said Yang. “We are excited to explore the potential of developing gene therapies to halt the progression of neurodegenerative disease.”
This research was supported by the National Institutes of Health and funding received by Penn under a sponsored research agreement with Wealth Strategy Holding Limited.
Note: Yang has patents and patent applications related to TRIM proteins owned by the University of Pennsylvania and holds equity in Evergreen Therapeutics LLC, which received investments from Wealth Strategy Holding Limited. Penn and Yang may receive financial consideration related to the licensing of certain Penn intellectual property to Evergreen Therapeutics LLC in the future.