Weizmann
Institute of Science researchers discover a new neuroprotective pathway
Genetic mutations linked to a disease
often spell bad news. Mutations in over 25 genes, for example, are associated
with amyotrophic lateral sclerosis, or ALS, and they all increase the risk of
developing this incurable disorder. Now, a research team headed by Prof. Eran
Hornstein of the Weizmann Institute of Science has linked a new gene to ALS,
but this one contains mutations of a different sort: They seem to play a
defensive, rather than an offensive, role in the disease.
The gene newly linked to ALS is
located in the part of our genome once called “junk DNA.” This DNA makes up
over 97 percent of the genome, but because it does not encode proteins, it used
to be considered, well, junk. Today, though this noncoding DNA is still
regarded as biological dark matter, it’s already known to serve as a crucial
instruction manual. Among other things, it determines when genes within the
coding DNA – the ones that do encode proteins – are turned on and off.
Hornstein’s lab in Weizmann’s Molecular Neuroscience and Molecular Genetics
Departments studies neurodegenerative diseases – that is, diseases in which
neurons degenerate and die. The team is focusing on our noncoding DNA. “This
massive, noncoding part of the genome has been overlooked in the search for the
genetic origins of neurodegenerative diseases like ALS,” Hornstein explains.
“This is despite the fact that for most ALS cases, proteins cannot explain the
emergence of the disease.”
Many people know about ALS thanks to
the Ice Bucket Challenge that went viral a few years ago. This rare
neurological disease attacks motor neurons, the nerve cells responsible for
controlling voluntary muscle movement involved in everything from walking to
talking and breathing. The neurons gradually die off, ultimately causing respiratory
failure and death. One of the symptoms of ALS is inflammation in the brain
regions connected to the dying neurons, caused by immune mechanisms in the
brain.
“Our brain has an immune system,”
explains Dr. Chen Eitan, who led the study in Hornstein’s lab together with
Aviad Siany. “If you have a degenerative disease, your brain’s immune cells,
called microglia, will try to protect you, attacking the cause of the
neurodegeneration.”
The problem is that in ALS, the
neurodegeneration becomes so severe that the chronic microglial activation in
the brain rises to extremely high levels, turning toxic. The immune system thus
ends up causing damage to the brain it set out to protect, leading to the death
of more motor neurons.
That’s where the new findings,
published today in Nature Neuroscience, come in. The Weizmann scientists
focused on a gene called IL18RAP, long known to affect microglia, and found
that it can contain mutations that mitigate the microglia’s toxic effects. “We
have identified mutations in this gene that reduce inflammation,” Eitan says.
After analyzing the genomes of more
than 6,000 ALS patients and of more than 70,000 people who do not have ALS, the
researchers concluded that the newly identified mutations reduce the risk of
developing ALS nearly fivefold. It is therefore extremely rare for ALS patients
to have these protective mutations, and those rare patients who do harbor them
tend to develop the disease roughly six years later, on average, than those
without the mutations. In other words, the mutations seem to be linked to a
core ALS process, slowing the disease down.
To confirm
the findings, the researchers used gene-editing technology to introduce the
protective mutations into stem cells from patients with ALS, causing these
cells to mature into microglia in a laboratory dish. They then cultured microglia, with or without the
protective mutations, in the same dishes with motor neurons. Microglia
harboring the protective mutations were found to be less aggressive toward
motor neurons than microglia that did not have the mutations. “Motor neurons
survived significantly longer when cultured with protective microglia, rather
than with regular ones,” Siany says.
Eitan notes that the findings have
potential implications for ALS research and beyond. “We’ve found a new
neuroprotective pathway,” she says. “Future studies can check whether
modulating this pathway may have a positive effect on patients. On a more
general level, our findings indicate that scientists should not ignore noncoding
regions of DNA – not just in ALS research, but in studying other diseases with
a genetic component as well.”
Prof. Eran Hornstein’s research is
supported by the Andrea L. and Lawrence A. Wolfe Family Center for Research on
Neuroimmunology and Neuromodulation; the Kekst Family Institute for Medical
Genetics; the Weizmann-Brazil Center for Neurodegeneration Research; the Nella
and Leon Benoziyo Center for Neurological Diseases; the Goldhirsh-Yellin
Foundation; the Redhill Foundation – Sam and Jean Rothberg Charitable Trust;
and the Dr. Dvora and Haim Teitelbaum Endowment Fund.
Prof. Hornstein is the incumbent of
the Mondry Family Professorial Chair.
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