Mutations in Noncoding DNA Are Found to Protect the Brain From ALS – Neuroscience News

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

Source: Weizmann Institute of Science

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 junk.

Today, though this noncoding DNA is still regarded as biological dark matter, its already known to serve as a crucial instruction manual. Among other things, it determines whengeneswithin the coding DNAthe ones that do encode proteinsare turned on and off.

Hornsteins lab in Weizmanns Molecular Neuroscience and Molecular Genetics Departments studies neurodegenerative diseasesthat 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 Hornsteins lab together with Aviad Siany. If you have a degenerative disease, your brains immune cells, calledmicroglia, 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 thebrainit set out to protect, leading to the death of more motor neurons.

Thats where the new findings, published today inNature 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 microglias 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 towardmotor neuronsthan microglia that did not have themutations.

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. Weve 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 DNAnot just in ALS research, but in studying other diseases with a genetic component as well.

Author: Press OfficeSource: Weizmann Institute of ScienceContact: Press Office Weizmann Institute of ScienceImage: The image is in the public domain

Original Research: Closed access.Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3UTR protect against ALS by Chen Eitan et al. Nature Neuroscience

Abstract

Whole-genome sequencing reveals that variants in the Interleukin 18 Receptor Accessory Protein 3UTR protect against ALS

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

Here, we performed region-based rare variant association analysis 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 interleukin-18 receptor accessory protein (IL18RAP) 3 untranslated region (3UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS, and this was replicated in an independent cohort. These variants in theIL18RAP3UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins.

Finally, the variants of theIL18RAP3UTR confer a survival advantage for motor neurons because they dampen neurotoxicity of human induced pluripotent stem cell (iPSC)-derived microglia bearing an ALS-associated expansion inC9orf72, and this depends on NF-B signaling.

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

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Mutations in Noncoding DNA Are Found to Protect the Brain From ALS - Neuroscience News