Altered fat metabolism, enzyme, likely plays key role in Lou Gehrig's
disease

Date:
November 15, 2021
Source:
Johns Hopkins Medicine
Summary:
A new study using genetically engineered mice and human cell
and tissue samples has added to evidence that higher levels
of inflammatory chemicals involved in fat metabolism occur in
people with amyotrophic lateral sclerosis (ALS), the neuromuscular
disorder, also known as Lou Gehrig's disease.



FULL STORY ==========================================================================
A new study using genetically engineered mice and human cell and
tissue samples has added to evidence that higher levels of inflammatory chemicals involved in fat metabolism occur in people with amyotrophic
lateral sclerosis (ALS), the neuromuscular disorder, also known as Lou
Gehrig's disease.


==========================================================================
The study, which focused on genetic pathways involved in how spinal
motor cells process fats, found that compared with people without ALS,
those with the disorder have about 2.5-fold higher levels of arachidonic
acid, a lipid commonly found in the fatty parts of meat and fish and
that is known to spur on inflammatory processes needed to repair wounds
or tissue damage.

Notably, by tampering with the arachidonic acid pathway in mice bred to
develop the biological hallmarks of ALS, the researchers say they were
able to reduce the condition's muscle-weakening symptoms in the mice --
which experienced a 20%-25% increase in grip strength -- and extend
their survival by two to three weeks.

A report on the work, led by Johns Hopkins Medicine researchers, appears
in the Nov. 15 issue of Nature Neuroscience.

The scientists used caffeic acid, an anti-inflammatory compound found
naturally in coffee, tea, tomatoes and wine, to tamp down the arachidonic
acid pathway, but they caution that people with ALS should not rush to
treat themselves with the substance, which is sold as an unregulated
dietary supplement. More studies are needed to determine safe levels
of a caffeic acid supplement -- some reports have indicated potentially
harmful side effects, including cancers and gut problems.

Also sold in alleged muscle enhancement powders, arachidonic acid in inappropriate and untested amounts can be toxic, triggering brain cells
to die off, experts say.



==========================================================================
Some 30,000 people in the U.S. have ALS, according to the researchers, and about 10% of cases can be attributed to heritable genetic alterations. The
rest occur sporadically. There is no known curative treatment.

The new study built on the established observation that though patients
with ALS lose most of their muscle control because of damaged spinal
motor neurons, generally they can still control their eye movements,
which are guided by ocular neurons, says Gabsang Lee, D.V.M., Ph.D.,
associate professor of neurology at the Johns Hopkins University School
of Medicine and member of the Institute for Cell Engineering at Johns
Hopkins Medicine.

To explore the potentially important genetic differences between
disease-free ocular neurons and spinal motor neurons that bear the brunt
of ALS, Lee's team studied stem cell lines they cultivated from a person
with ALS. Looking at the genetic pathways actively making proteins, the scientists found more activity in genes that control lipid metabolism --
the process in which cells process fat.

Lee then sent to colleagues at the University of Southern California
samples of ocular neurons and spinal motor neurons from 17 people with
ALS who were treated at The Johns Hopkins Hospital, and six sample sets
of people without the condition. The researchers confirmed that spinal
motor neurons of the people with ALS contained completely different
amounts and types of lipids than did ocular neurons, compared to people
without the condition.

Further analysis to identify which lipid pathways were most altered
between cells of people with ALS and cells of people without the disease
showed that one pathway stood out -- arachidonic acid.



==========================================================================
An omega-6 fatty acid that controls the body's inflammatory response, arachidonic acid has been linked to Alzheimer's and Parkinson's diseases
and, two decades ago, researchers found higher than expected amounts of
the enzyme in neuromuscular tissue of people with ALS.

Lee says lipid pathways have been highly studied because they are critical parts of the cell membrane, that enable the flow of molecules in and out
of cells. Cell membranes often break when there is inflammation, and Lee
says the body must tightly regulate arachidonic acid, or inflammation can
run amok and send signals to the immune system to destroy neural tissue.

To further test the role of arachidonic acid, the investigators performed experiments to reverse its effects by feeding caffeic acid first to
fruit flies genetically engineered to develop ALS-type symptoms. Flies
fed caffeic acid were able to move around more, climb up the test tube
more often and live longer than flies that did not receive the compound.

The scientists then conducted similar experiments with caffeic acid in
mice bred to develop ALS, and those that received the compound lived
two to three weeks longer than mice not fed the compound.

Although the new evidence may one day offer potential new strategies for therapy, Lee says that questions linger. "We don't know yet why ocular
and spinal neurons differ in lipid metabolism or what percentage of ALS patients have alterations in the arachidonic acid pathway," he says.

Lee has filed provisional patents for technology related to the potential
use of the arachidonic acid pathway to treat ALS.

Funding for the research was provided by the Robert Packard Center
for ALS Research, the National Institutes of Health (R01NS093213), the
National Research Foundation of Korea, the Donald E. and Delia V. Baxter Foundation, and the Department of Molecular Microbiology and Immunology
at the University of Southern California.

In addition to Lee, scientists who conducted the research are Hojae
Lee, Sandeep Kumar Dubey, Kai Ruan, Seong-Hyun Park, Shinwon Ha, Irina Kovlyagina, Seongjun Kim, Yohan Oh, Hyesoo Kim, Sung-Ung Kang, Thomas
Lloyd and Nicholas Maragakis from Johns Hopkins; Jae Jin Lee and Hyungjin
Eoh from the University of Southern California; Na Young Park and Young
Bin Hong from Dong-A University in South Korea; Taeyong Kim from San
Diego State University; Su Bin Lim from the Ajou University School of
Medicine in South Korea, and Kyung-tai Kim and Mi-Ryoung Song from the
Gwangju Institute of Science and Technology in South Korea.

========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hojae Lee, Jae Jin Lee, Na Young Park, Sandeep Kumar Dubey,
Taeyong Kim,
Kai Ruan, Su Bin Lim, Seong-Hyun Park, Shinwon Ha, Irina Kovlyagina,
Kyung-tai Kim, Seongjun Kim, Yohan Oh, Hyesoo Kim, Sung-Ung Kang,
Mi- Ryoung Song, Thomas E. Lloyd, Nicholas J. Maragakis, Young Bin
Hong, Hyungjin Eoh, Gabsang Lee. Multi-omic analysis of selectively
vulnerable motor neuron subtypes implicates altered lipid metabolism
in ALS. Nature Neuroscience, 2021; DOI: 10.1038/s41593-021-00944-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211115123501.htm

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