Mutations in non-coding DNA have been found to protect the brain from ALS

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

Source: Weizmann Institute of Science

Genetic mutations associated with a disease often mean bad news. For example, mutations in over 25 genes are linked to amyotrophic lateral sclerosis, or ALS, and they all increase the risk of developing this incurable disease.

Now a team of researchers led by Weizmann Institute of Science professor Eran Hornstein has linked a new gene to ALS, but one that harbors mutations of a different nature: they appear to play a defensive rather than an offensive role in the disease.

The newly linked gene associated with ALS is located in the part of our genome that was once called ‘junk DNA’. This DNA makes up over 97 percent of the genome, but because it doesn’t encode proteins, it used to be considered “junk.”

Although this non-coding DNA is still considered biological dark matter today, it is already recognized as an important instruction manual. Among other things, it determines when genes within the coding DNA — the ones that encode proteins — turn on and off.

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

“This massive, non-coding part of the genome was overlooked in the search for the genetic origins of neurodegenerative diseases such as ALS,” explains Hornstein.

“And this despite the fact that in most cases of ALS, proteins cannot explain the development of the disease.”

Many people know about ALS thanks to the Ice Bucket Challenge that went viral a few years ago. This rare neurological disorder attacks motor neurons, the nerve cells responsible for controlling voluntary muscle movements involved in everything from walking to speaking to breathing.

The neurons gradually die, eventually leading to respiratory failure and death. One of the symptoms of ALS is inflammation in the brain regions associated with 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 along 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.”

Photo credit: Weizmann Institute of Science

The problem is that in ALS, the neurodegeneration becomes so severe that chronic microglial activation in the brain rises to extremely high levels and becomes toxic. So the immune system ends up damaging the brain it’s designed to protect, leading to the death of more motor neurons.

These are the new findings published today in nature neuroscienceThe Weizmann scientists focused on a gene called IL18RAP, which has long been known to affect microglia, and found that it may harbor mutations that weaken the toxic effects of the microglia. “We have identified mutations in this gene that reduce inflammation,” says Eitan.

After analyzing the genomes of more than 6,000 ALS patients and more than 70,000 people who don’t have ALS, the researchers concluded that the newly identified mutations increase the risk of developing ALS almost fivefold.

The newly linked gene associated with ALS is located in the part of our genome that was once called ‘junk DNA’. The image is in the public domain

It is therefore extremely rare for ALS patients to have these protective mutations, and the rare patients who harbor them develop the disease, on average, about six years later than those without the mutations. In other words, the mutations appear to be linked to a central ALS process that slows down the disease.

To confirm the results, 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 shells as motor neurons. It was found that microglia with the protective mutations are less aggressive towards motoneurons than microglia without the mutations.

“Motor neurons survived significantly longer when cultured with protective microglia than with normal ones,” says Siany.

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

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“Future studies can examine whether modulation of this pathway can have a positive effect on patients. On a more general level, our results indicate that scientists should not ignore non-coding regions of DNA, not only in ALS research but also when studying other diseases with a genetic component.”

About this news from genetics and ALS research

Author: press office
Source: Weizmann Institute of Science
Contact: Press Office – Weizmann Institute of Science
Image: The image is in the public domain

Original research: Closed access.
Whole genome sequencing shows that variants of the interleukin-18 receptor accessory protein 3’UTR protect against ALS‘ by Chen Eitan et al. nature neuroscience


abstract

Whole genome sequencing shows that variants of the interleukin-18 receptor accessory protein 3’UTR 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 association analysis of rare variants of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole genomes and the whole genomes of 70,403 non-ALS controls.

We identified the interleukin-18 receptor accessory protein (IL18RAP) variants of the 3′-untranslated region (3′UTR) found to be 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 variants in the IL18RAP 3’UTRs reduce mRNA stability and binding of double-stranded RNA (dsRNA)-binding proteins.

Finally, the variants of the IL18RAP 3’UTRs confer a survival advantage to motoneurons by attenuating the neurotoxicity of human induced pluripotent stem cell (iPSC) microglia with an ALS-associated expansion C9orf72and this depends on NF-κB signalling.

This study uncovers genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies.

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