Look deep inside the brain of someone with Alzheimer's disease, most forms
of dementia or the concussion-related syndrome known as chronic traumatic
encephalopathy (CTE) and you'll find a common suspected culprit: stringy,
hairball-like tangles of a protein called tau.
Such conditions, collectively known as "tauopathies" strike scores of people
across the globe, with Alzheimer's alone affecting six million people in the
United States.
But more than a century after German psychiatrist Alois Alzheimer discovered
tau tangles, scientists still have much to learn about them.
A University of Colorado Boulder study, published this week in the journal
Neuron, shows for the first time that tau aggregates gobble up RNA, or
ribonucleic acid, inside cells and interfere with an integral mechanism
called splicing, by which cells ultimately produce needed proteins.
"Understanding how tau leads to neurodegeneration is the crux of not just
understanding Alzheimer's disease but also multiple other neurological
diseases," said senior author Roy Parker, a professor of biochemistry and
director of the BioFrontiers Institute at CU Boulder. "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."
The study was led by Evan Lester, an M.D./PhD candidate in the Medical
Scientist Training Program, which enables students to simultaneously work
toward a medical degree from the University of Colorado Anschutz Medical
Campus and a PhD from CU Boulder.
For part of his medical training, Lester worked alongside doctors and
patients at the CU Alzheimer's and Cognition Center in Aurora.
"There is nothing we can do for these patients right now - no disease
modifying-treatments for Alzheimer's or most of the other tauopathies,"
Lester said, noting that 70% of neurodegenerative diseases are believed to
be at least partially related to tau aggregates.
For the study, the researchers isolated tau aggregates from cell lines and
from the brains of mice with an Alzheimer's-like condition. Then they used
genetic sequencing techniques to determine what was inside.
They confirmed for the first time that tau aggregates contain RNA, or
ribonucleic acid, a single-stranded molecule key for synthesizing proteins
in cells. They identified what kind of RNA it is, specifically snRNA, or
small nuclear RNA, and snoRNA, or small nucleolar RNA.
They also discovered that tau interacts with pieces of cellular machinery
known as nuclear speckles, sequestering and displacing proteins inside them
and disrupting a process called RNA splicing in which the cell weeds out
unneeded material to generate new, healthy 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," said Lester.
Notably, scientists examining the brains of Alzheimer's patients after death
have discovered evidence of splicing-related defects in cells.
The paper is the first in a series out of Parker's lab to explore the
mechanism of action by which tau aggregates gum up the works inside brain
cells.
Already, several companies have clinical trials underway testing drugs that
would do away with tau entirely in patients with neurodegenerative diseases.
But that could potentially have unintended consequences, said Lester.
"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,"
he said.
By better understanding precisely what it does to harm and kill cells,
Parker and Lester hope to bring a different approach to the table.
"The idea would be to intervene in the abnormal functions while preserving
the normal functions of tau," Lester said.
Reference:
Evan Leicester etc. Tau aggregates are RNA-protein aggregates that mislocalize
multiple nuclear speckle components. Neuron (2021). DOI:
10.1016/j.neuron.2021.03.026