New research from the Perelman School of Medicine at the University of Pennsylvania has revealed exciting findings regarding the gene encoding the tripartite motif protein 11 (TRIM11) and its role in neurodegenerative diseases similar to Alzheimer’s disease (AD). The study, published in Science, demonstrates that TRIM11 can suppress deterioration in small animal models of neurodegenerative diseases and improve cognitive and motor abilities. Additionally, TRIM11 was found to play a key role in removing the protein tangles associated with AD and other neurodegenerative diseases.
AD is a prevalent cause of dementia among older adults, affecting around 6 million Americans. The disease progressively impairs memory and cognitive functions. The research led by Dr. Virginia M.Y. Lee and the late Dr. John Q. Trojanowski at Penn Medicine revealed that neurofibrillary tangles (NFTs) of tau proteins are one of the underlying causes of neurodegenerative diseases. These tau proteins lead to neuronal death, resulting in the characteristic symptoms of AD.
Tau proteins are also associated with other dementias and movement disorders collectively known as tauopathies, including progressive supranuclear palsy, Pick’s disease, and chronic traumatic encephalopathy. However, the exact mechanisms of how tau proteins aggregate and form NFTs in patients with these diseases have remained unclear, posing a challenge to developing effective therapies.
Dr. Xiaolu Yang, a professor of Cancer Biology at Penn and the senior author of the study, explained that most organisms possess protein quality control systems that remove defective proteins and prevent the accumulation of tangles. The team’s research focused on understanding this process in humans, particularly how it malfunctions in some individuals and not others.
The study identified TRIM11 as the gene responsible for overseeing tau function. TRIM proteins are known for their role in protein quality control in animal cells. The researchers found that TRIM11 plays a significant role in suppressing tau aggregation through three main functions: binding to tau proteins, acting as a “chaperone” to prevent mis-folding, and dissolving pre-existing tau aggregates.
To validate their findings, the researchers used postmortem brain tissues from individuals with AD and healthy controls. They found substantially reduced levels of TRIM11 protein in the brains of individuals with AD compared to healthy controls.
To explore the therapeutic potential of TRIM11, the team used adeno-associated viral vectors (AAV) commonly employed in gene therapy to deliver the TRIM11 gene into the brains of mouse models with tau pathologies. Remarkably, mice receiving the TRIM11 gene demonstrated a marked decrease in NFT development and accumulation, accompanied by significantly improved cognitive and motor abilities.
Dr. Yang emphasized the promising role of TRIM11 in protecting individuals from Alzheimer’s and other related neurodegenerative diseases. He envisions the possibility of developing gene therapies that could replenish TRIM11 in individuals with lower levels of the protein, potentially halting the progression of neurodegenerative diseases.
The study was supported by the National Institutes of Health and funding from Penn through a sponsored research agreement with Wealth Strategy Holding Limited. Dr. Xiaolu Yang is associated with patents and patent applications related to TRIM proteins at the University of Pennsylvania. He is also a co-founder and equity holder of Evergreen Therapeutics LLC, which received investments from Wealth Strategy Holding Limited. As such, financial considerations related to the licensing of certain Penn intellectual property to Evergreen Therapeutics LLC may be relevant.
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Materials provided by University of Pennsylvania School of Medicine. Note: Content may be edited for style and length.
Journal Reference:
- Zi-Yang Zhang, Dilshan S. Harischandra, Ruifang Wang, Shivani Ghaisas, Janet Y. Zhao, Thomas P. McMonagle, Guixin Zhu, Kenzo D. Lacuarta, Jianing Song, John Q. Trojanowski, Hong Xu, Virginia M.-Y. Lee, Xiaolu Yang. TRIM11 protects against tauopathies and is down-regulated in Alzheimer’s disease. Science, 2023; 381 (6656) DOI: 10.1126/science.add6696