Mutations in noncoding DNA found to protect brain from ALS





Summary: Mutations in the IL18RAP gene reduce inflammation and appear to protect the brain against ALS.

Source: Weizmann Institute of Science

Disease-related genetic mutations are often synonymous with bad news. Mutations in more than 25 genes, for example, are associated with amyotrophic lateral sclerosis, or ALS, and they all increase the risk of developing this incurable disease.

Now a research team led by Professor Eran Hornstein of the Weizmann Institute of Science has linked a new gene to ALS, but it contains mutations of a different type: they appear to play a defensive role rather than offensive in disease.

The newly linked ALS gene is located in the part of our genome once called “junk DNA”. This DNA makes up more than 97% of the genome, but because it doesn’t code for proteins, it was once considered ‘junk’.

Today, although this non-coding DNA is still considered biological dark matter, it is already known to serve as a crucial instruction manual. Among other things, it determines when genes within coding DNA – those that code for proteins – are turned on and off.

Hornstein’s lab in Weizmann’s Departments of Molecular Neuroscience and Molecular Genetics studies neurodegenerative diseases, that is, diseases in which neurons degenerate and die. The team is focusing on our non-coding DNA.

“This massive, non-coding part of the genome has been overlooked in the search for the genetic origins of neurodegenerative diseases like ALS,” says Hornstein.

“This despite the fact that for most cases of ALS, proteins cannot explain the emergence of the disease.”

Many people know about ALS from 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 speaking and breathing.

Neurons gradually die, eventually causing respiratory failure and death. One of the symptoms of ALS is inflammation of brain regions connected to dying neurons, caused by immune mechanisms in the brain.

“Our brain has an immune system,” says Dr. Chen Eitan, who led the study in Hornstein’s lab with Aviad Siany. “If you have a degenerative disease, your brain’s immune cells called microglia will try to protect you by attacking the cause of the neurodegeneration.”

Credit: Weizmann Institute of Science

The problem is that in ALS, the neurodegeneration becomes so severe that the chronic activation of microglia in the brain reaches extremely high levels, becoming toxic. The immune system thus ends up damaging the brain it was supposed to protect, leading to the death of a greater number of motor neurons.

This is where the new findings, published today in Natural neuroscience, enter. The Weizmann scientists focused on a gene called IL18RAP, which has long been known to affect microglia, and discovered that it may contain mutations that mitigate the toxic effects of microglia. “We have identified mutations in this gene that reduce inflammation,” Eitan explains.

After analyzing the genomes of more than 6,000 patients with ALS and more than 70,000 people without ALS, the researchers concluded that the newly identified mutations reduce the risk of developing ALS by almost five times.

It shows a brain
The newly linked ALS gene is located in the part of our genome once called “junk DNA”. Image is in public domain

It is therefore extremely rare for ALS patients to have these protective mutations, and the rare patients who harbor them tend to develop the disease about six years later, on average, than those who do not have the mutations. In other words, the mutations seem to be linked to a central process in ALS, slowing down the disease.

To confirm the results, the researchers used gene-editing technology to introduce the protective mutations into the stem cells of ALS patients, causing those cells to mature into microglia in a lab 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 lacked the mutations.

“The motor neurons survived much longer when cultured with protective microglia, rather than with regular microglia,” Siany explains.

Eitan notes that the findings have potential implications for ALS research and beyond. “We have found a new neuroprotective pathway,” she says.

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“Future studies can test whether modulating this pathway can have a positive effect on patients. On a more general level, our findings indicate that scientists should not ignore non-coding regions of DNA, not just in ALS research, but also in the study of other diseases with genetic components.

About this genetics and ALS research news

Author: Press office
Source: Weizmann Institute of Science
Contact: Press Service – Weizmann Institute of Science
Picture: Image is in public domain

Original research: Access closed.
“Whole-genome sequencing reveals that variants of the interleukin 18 receptor 3′UTR accessory protein protect against ALS” by Chen Eitan et al. Natural neuroscience


Abstract

Whole-genome sequencing reveals variants of the 3′UTR accessory protein of the interleukin-18 receptor protect against ALS

The non-coding genome is substantially larger than the protein-coding genome, but has been largely unexplored by genetic association studies.

Here, we performed a region-based rare variant association analysis of >25,000 variants in untranslated regions of 6,139 whole amyotrophic lateral sclerosis (ALS) genomes and whole genomes of 70,403 non-ALS controls.

We have identified the interleukin-18 receptor accessory protein (IL18RAP) 3′ untranslated region (3′UTR) variants are significantly enriched in non-ALS genomes and associated with a five-fold reduced risk of developing ALS, and this was replicated in an independent cohort. These variations in the IL18RAP 3’UTRs reduce mRNA stability and binding of double-stranded RNA (dsRNA) binding proteins.

Finally, the variants of IL18RAP 3′UTRs confer a survival advantage to motor neurons as they attenuate the neurotoxicity of microglia derived from human induced pluripotent stem cell (iPSC) bearing expansion associated with ALS in C9orf72and it depends on NF-κB signaling.

This study reveals genetic variants that protect against ALS by reducing neuroinflammation and highlights the importance of non-coding genetic association studies.




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