One of the big mysteries in biology is why cells age. Now scientists at
the Salk Institute for Biological Studies report that they have
discovered a weakness in a component of brain cells that may explain how
the aging process occurs in the brain.
The scientists discovered that certain proteins, called extremely
long-lived proteins (ELLPs), which are found on the surface of the
nucleus of neurons, have a remarkably long lifespan.
While the lifespan of most proteins totals two days or less, the Salk
Institute researchers identified ELLPs in the rat brain that were as
old as the organism, a finding they reported February 3 in Science.
The Salk scientists are the first to discover an essential
intracellular machine whose components include proteins of this age.
Their results suggest the proteins last an entire lifetime, without
being replaced.
ELLPs make up the transport channels on the surface of the nucleus;
gates that control what materials enter and exit. Their long lifespan
might be an advantage if not for the wear-and-tear that these proteins
experience over time. Unlike other proteins in the body, ELLPs are not
replaced when they incur aberrant chemical modifications and other
damage.
Damage to the ELLPs weakens the ability of the three-dimensional
transport channels that are composed of these proteins to safeguard the
cell's nucleus from toxins, says Martin Hetzer, a professor in Salk's
Molecular and Cell Biology Laboratory, who headed the research. These
toxins may alter the cell's DNA and thereby the activity of genes,
resulting in cellular aging.
Funded by the Ellison Medical Foundation and the Glenn Foundation for
Medical Research, Hetzer's research group is the only lab in the world
that is investigating the role of these transport channels, called the
nuclear pore complex (NPC), in the aging process.
Previous studies have revealed that alterations in gene expression
underlie the aging process. But, until the Hetzer lab's discovery that
mammals' NPCs possess an Achilles' heel that allows DNA-damaging toxins
to enter the nucleus, the scientific community has had few solid clues
about how these gene alterations occur.
"The fundamental defining feature of aging is an overall decline in
the functional capacity of various organs such as the heart and the
brain," says Hetzer. "This decline results from deterioration of the
homeostasis, or internal stability, within the constituent cells of
those organs. Recent research in several laboratories has linked
breakdown of protein homeostasis to declining cell function."
The results that Hetzer and his team just report suggest that
declining neuron function may originate in ELLPs that deteriorate as a
result of damage over time.
"Most cells, but not neurons, combat functional deterioration of
their protein components through the process of protein turnover, in
which the potentially impaired parts of the proteins are replaced with
new functional copies," says Hetzer.
"Our results also suggest that nuclear pore deterioration might be a
general aging mechanism leading to age-related defects in nuclear
function, such as the loss of youthful gene expression programs," he
adds.
The findings may prove relevant to understanding the molecular
origins of aging and such neurodegenerative disorders as Alzheimer's
disease and Parkinson's disease.
In previous studies, Hetzer and his team discovered large filaments
in the nuclei of neurons of old mice and rats, whose origins they traced
to the cytoplasm. Such filaments have been linked to various
neurological disorders including Parkinson's disease. Whether the
misplaced molecules are a cause, or a result, of the disease has not yet
been determined.
Also in previous studies, Hetzer and his team documented
age-dependent declines in the functioning of NPCs in the neurons of
healthy aging rats, which are laboratory models of human biology.
Hetzer's team includes his colleagues at the Salk Institute as well
as John Yates III, a professor in the Department of Chemical Physiology
of The Scripps Research Institute.
When Hetzer decided three years ago to investigate whether the NPC
plays a role in initiating or contributing to the onset of aging and
certain neurodegenerative diseases, some members of the scientific
community warned him that such a study was too bold and would be
difficult and expensive to conduct. But Hetzer was determined despite
the warnings.
Journal Reference:
- J. N. Savas, B. H. Toyama, T. Xu, J. R. Yates, M. W. Hetzer. Extremely Long-Lived Nuclear Pore Proteins in the Rat Brain. Science, 2012; DOI: 10.1126/science.1217421
Courtesy: ScienceDaily
No comments:
Post a Comment