Stress-sensing Molecule May Be Potential Therapeutic Target in ALS

A small molecule called microRNA-182-5p (miR‐182‐5p) is involved in the detection of cell stress and in the survival of motor neurons, the cells progressively lost in people in amyotrophic lateral sclerosis (ALS), a study in mice showed.

These findings shed light on the mechanisms behind ALS’ stress-associated nerve cell death and provide new potential therapeutic targets.

The study, “MicroRNA‐183‐5p is stress‐inducible and protects neurons against cell death in amyotrophic lateral sclerosis,” was published in the Journal of Cellular and Molecular Medicine.

MicroRNAs, or miRNAs, are small RNA molecules that target a specific gene’s messenger RNA (mRNA) — the genetic blueprint derived from DNA and used as a template for protein production — to prevent generation of that protein. A single miRNA can regulate several mRNAs.

Increasing evidence suggests that miRNAs’ dysregulation contributes to neurodegeneration in ALS patients, which may help to identify new diagnostic biomarkers and develop new therapeutic approaches for ALS.

Notably, miRNAs were found to be involved in the detection and response to cell stress including oxidative stress, which promotes the toxic build-up of TDP-43 clumps, problems in mitochondria (the cells’ powerhouses), and nerve cell death in ALS.

Oxidative stress is an imbalance in the production of harmful molecules called reactive oxygen species that can lead to cell damage and death.

While problems in stress detection or response may contribute to nerve cell death in ALS, such underlying mechanisms remain largely unknown.

Researchers at West China Hospital of Sichuan University, in China, now have discovered that miR‐182‐5p, a microRNA known to be dysregulated in several cancers, is highly present in motor neurons — nerve cells that control voluntary muscle movement — and regulates stress-sensing mechanisms and cell death in a mouse model of ALS.

The team first found that while miR‐182‐5p was detected in several organs and tissues of healthy mice, its highest levels were present in the spinal cord, particularly in the region containing motor neurons.

The researchers then assessed whether miR‐182‐5p levels in the spinal cord were different between healthy mice and a mouse model of ALS.

Mice with ALS had significantly higher miR‐182‐5p levels in the pre-symptomatic and early symptomatic stages of the disease and significantly lower levels in the late stages, compared with healthy mice.

This drop in miR‐182‐5p levels in late ALS stages may be related to its characteristic, progressive loss of motor neurons, the researchers noted.

Database analyses identified a total of 399 potential genes targeted by miR‐182‐5p, which were involved mainly in cell stress responses and cell death. Further tests in lab-grown mouse nerve cells, including motor neurons, showed that miR‐182‐5p was produced in response to several stress conditions associated with ALS.

These included oxidative stress, endoplasmic reticulum stress (a kind of stress response to defective protein production), and tumor necrosis factor (TNF) alpha, an inflammatory molecule.

Notably, blocking miR‐182‐5p in nerve cells under such stress conditions led to a drastic increase in cell death, while promoting higher-than-normal levels of miR‐182‐5p had a protective effect.

Further analysis revealed that miR‐182‐5p regulates nerve cell death by directly suppressing PDCD4 — a critical protein in apoptosis, the natural process of programmed cell death — and RIPK3 — a well‐known regulator of necroptosis, a form of inflammatory cell death associated with motor neuron death in ALS.

These findings highlight that miR‐183‐5p “is not only a stress sensor in motor neurons, but also an executive factor in neuron death programming,” the researchers wrote, noting that it “protects neurons against cell death under stress conditions.”

“Our study supplements current understanding of the mechanistic link between cell stress and death/survival, and provides novel targets for clinical interventions of ALS,” the team wrote, adding that increasing the levels of miR‐183‐5p may potentially prevent motor neuron death in ALS.

Given that a previous study showed that white blood cells of Chinese ALS patients had significantly lower levels of miR‐182‐5p, compared with those of healthy people, miR‐183‐5p may have a systemic (body-wide) role in ALS, the researchers noted.