Monday, April 04, 2022

Mutations in Noncoding DNA Protect the Brain from ALS

Good 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 ... 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 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,” ...
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,”"

From the abstract:
"... 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 (3′UTR) 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 the IL18RAP 3′UTR reduce mRNA stability and the binding of double-stranded RNA (dsRNA)-binding proteins. Finally, the variants of the IL18RAP 3′UTR 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 in C9orf72, and this depends on NF-κB signaling. This study reveals genetic variants that protect against ALS by reducing neuroinflammation and emphasizes the importance of noncoding genetic association studies."

Mutations in Noncoding DNA Protect the Brain from ALS - Life Sciences | Weizmann Wonder Wander - News, Features and Discoveries Weizmann Institute of Science researchers discover a new neuroprotective pathway

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