If looked deep into the brain of a patient with Alzheimer’s disease or those suffering from the most types of dementia or the concussion-associated syndrome, called chronic traumatic encephalopathy (CTE), there would be hairball-like tangles of a protein known as tau—a common suspected culprit.
Evan Lester. Image Credit: University of Colorado at Boulder.
These disorders collectively called “tauopathies,” affect an unlimited number of people worldwide, with Alzheimer’s disease alone affecting six million individuals in the United States.
Although tau tangles were discovered by German psychiatrist Alois Alzheimer more than a century ago, researchers still need to learn more about them.
For the first time, a study performed by the University of Colorado at Boulder (CU Boulder) and recently published in the Neuron journal demonstrated that tau aggregates ingest RNA, also known as ribonucleic acid, within the cells and disrupt an integral mechanism, known as splicing, through which cells eventually create the required proteins.
Understanding how tau leads to neurodegeneration is the crux of not just understanding Alzheimer’s disease but also multiple other neurological diseases. If we can understand what it does and how it goes bad in disease we can develop new therapies for conditions that now are largely untreatable.”
Roy Parker, Study Senior Author and Professor, Biochemistry, University of Colorado at Boulder
Parker is also the director of CU Boulder’s BioFrontiers Institute. The research work was headed by Evan Lester, an MD/Ph.D. candidate in the Medical Scientist Training Program. This program allows students to concurrently work toward a Ph.D. from CU Boulder and a medical degree from the University of Colorado Anschutz Medical Campus.
As part of his medical training, Lester worked along with patients and doctors at the CU Alzheimer’s and Cognition Center in Aurora, where he personally witnessed how crucially more research works are needed.
“There is nothing we can do for these patients right now – no disease modifying-treatments for Alzheimer’s or most of the other tauopathies,” said Lester, noting that tau aggregates could be partly involved in 70% of neurodegenerative diseases.
During the study, the researchers extracted tau aggregates from cell lines and also from the brains of mice with a condition mimicking Alzheimer’s disease. Then, using genetic sequencing methods, they determined what was inside.
For the first time, the team confirmed that tau aggregates contain RNA, a single-stranded molecule crucial for protein synthesis in cells. They figured out what kind of RNA it is: particularly snoRNA, or small nucleolar RNA and snRNA, or small nuclear RNA.
The researcher also discovered that tau aggregates interact with nuclear speckles, which are pieces of cellular machinery that sequester and displace proteins within them and disrupt a mechanism, known as RNA splicing, where the cell weeds out unnecessary material to produce new, healthier RNA.
The tau aggregates appear to be sequestering splicing-related RNA and proteins, disrupting their normal function and impairing the cell’s ability to make proteins.”
Evan Lester, MD/PhD Candidate, Medical Scientist Training Program
Most significantly, investigators assessing the brains of Alzheimer’s patients after their death have found proof of splicing-related defects in cells.
The article is the first in a series of Parker’s laboratory to investigate the mechanism of action through which tau aggregates clog the functions of brain cells.
Several firms are already conducting clinical trials in patients with neurodegenerative disorders to test drugs that will completely eliminate tau in these individuals. However, according to Lester, this could lead to potential outcomes.
A big problem in the field is that no one really knows what tau does in healthy people and It likely has important functions when not in tangles.”
Evan Lester, M.D./PhD Candidate, Medical Scientist Training Program
Parker and Lester intend to bring a new approach to the table by precisely understanding what it does to damage and destroy cells.
“The idea would be to intervene in the abnormal functions while preserving the normal functions of tau,” concluded Lester.
Lester, E., et al. (2021) Tau aggregates are RNA-protein assemblies that mislocalize multiple nuclear speckle components. Neuron. doi.org/10.1016/j.neuron.2021.03.026.