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ALS Genomic Analysis Highlights Potential MicroRNA Contributor

NEW YORK – New research suggests alterations affecting a microRNA called miR-218 that is normally expressed in human motor neurons may contribute to some of the neuronal excitability changes observed in the brains of those with amyotrophic lateral sclerosis (ALS).

"ALS neuropathology establishes miR-218 as a marker of human motor neuron mass and well-being that is downregulated in ALS," senior author Eran Hornstein, a molecular geneticist at the Weizmann Institute of Science and the Project MinE ALS Sequencing Consortium, and his co-authors wrote.

The study, reported online today in Science Translational Medicine, "contributes to an emerging view of ALS as a disease with a prominent RNA component," the authors explained, "and suggests that miR-218 is a potential therapeutic target for motor neuron disease. 

Using miRNA in situ hybridization, laser capture microdissection, expression profiling, and other approaches, researchers from the Israel, the US, and elsewhere saw lower-than-usual levels of a motor neuron-specific miRNA called miR-218 in ALS, prompting a series of follow-up experiments in mouse or rat models and a whole-genome screen focused on thousands of individuals with or without ALS who were previously profiled for the Project MinE study.

Along with altered regulation of messenger RNAs targeted by miR-218 — including a potassium channel gene Kv10.1 with an apparent role in neuronal activity — the team tracked down half a dozen rare variants in a chromosome 5 precursor miRNA sequence called hsa-mir-218-2 in individuals with ALS.

Those variants appeared to be somewhat enriched in samples from ALS cases compared with almost 63,000 unaffected controls, the researchers reported. Their subsequent functional and small RNA sequencing analyses suggested that such miR-218 variants were linked to altered neuronal excitability and mRNA regulation, in part due to changes in the way miR-218 itself is produced.

In particular, the team suggested that rare miR-218 variants, such as those identified in genome sequences from the ALS-affected individuals, may produce versions of a precursor miRNA that are less apt to processing by DICER — a double-stranded RNA-cleaving enzyme known for lopping long pre-microRNA sequences into miRNAs and other short RNAs.

The investigators cautioned that further research is needed to get a clearer view of the factors that can impact regulation of and by miR-218, as well as other contributors to ALS. Even so, they noted that their current findings support the notion that "mutated miR-218 exhibits impaired biogenesis, providing a conceivable mechanism for insufficient regulation of neuronal activity."

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