Cells that normally nourish healthy brain cells called neurons
release toxic fatty acids after neurons are damaged, a new study in
rodents shows. This phenomenon is likely the driving factor behind most,
if not all, diseases that affect brain function, as well as the natural
breakdown of brain cells seen in aging, researchers say.
Previous research has pointed to astrocytes — a star-shaped glial
cell of the central nervous system — as the culprits behind cell death
seen in Parkinson’s disease and dementia, among other neurodegenerative
diseases. While many experts believed that these cells released a
neuron-killing molecule to “clear away” damaged brain cells, the
identity of this toxin has until now remained a mystery.
Led by researchers at NYU Grossman School of Medicine, the new
investigation provides what they say is the first evidence that tissue
damage prompts astrocytes to produce two kinds of fats, long-chain
saturated free fatty acids, and phosphatidylcholines. These fats then
trigger cell death in damaged neurons, the electrically active cells
that send messages throughout nerve tissue.
Publishing Oct. 6 in the journal Nature, the study also
showed that when researchers blocked fatty acid formation in mice, 75% of neurons survived compared with 10% when the fatty
acids were allowed to form. The researchers’ earlier work showed that
brain cells continued to function when shielded from astrocyte attacks.
“Our findings show that the toxic fatty acids produced by astrocytes
play a critical role in brain cell death and provide a promising new
target for treating, and perhaps even preventing, many neurodegenerative
diseases,” says study co-senior author Shane Liddelow PhD.
Liddelow, an assistant professor in the Department of Neuroscience
and Physiology at NYU Langone Health, adds that targeting these fats
instead of the cells that produce them may be a safer approach to
treating neurodegenerative diseases because astrocytes feed nerve cells
and clear away their waste. Stopping them from working altogether could
interfere with healthy brain function.
Although it remains unclear why astrocytes produce these toxins, it
is possible they evolved to destroy damaged cells before they can harm
their neighbors, says Liddelow. He notes that while healthy cells are
not harmed by the toxins, neurons become susceptible to the damaging
effects when they are injured, mutated, or infected by prions, the
contagious, misfolded proteins that play a major role in mad cow disease
and similar illnesses. Perhaps in chronic diseases like dementia, this
otherwise helpful process goes off track and becomes a problem, the
study authors say.
For the investigation, researchers analyzed the molecules released by
astrocytes collected from rodents. They also genetically engineered
some groups of mice to prevent the normal production of the toxic fats
and looked to see whether neuron death occurred after an acute injury.
“Our results provide what is likely the most detailed molecular map
to date of how tissue damage leads to brain cell death, enabling
researchers to better understand why neurons die in all kinds of
diseases,” says Liddelow, also an assistant professor in the Department
of Ophthalmology at NYU Langone.
Liddelow cautions that while the findings are promising, the genetic
techniques used to block the enzyme that produces toxic fatty acids in
mice are not ready for use in humans. As a result, the researchers next
plan is to explore safe and effective ways to interfere with the release
of the toxins in human patients. Liddelow and his colleagues had
previously shown these neurotoxic astrocytes in the brains of patients
with Parkinson’s, Huntington’s disease, and multiple sclerosis, among
Source: News Release
NYU Langone Health / NYU Grossman School of Medicine
October 6, 2021