Lower Levels of MicroRNA in ALS Patients Linked to Nerve Cell Damage

People with amyotrophic lateral sclerosis (ALS) have significantly lower levels of a small molecule called microRNA-335-5p (miR-335-5p), which promotes the degradation of mitochondria and nerve cell death, a study shows.

These findings suggest that dysregulation of miR-335-5p may contribute to neurodegeneration in ALS patients, which may be useful in developing new therapeutic strategies for the disease.

The study, “Downregulation of miR-335-5P in Amyotrophic Lateral Sclerosis Can Contribute to Neuronal Mitochondrial Dysfunction and Apoptosis,” was published in the journal Scientific Reports.

MicroRNAs, or miRNAs, are tissue-specific small molecules of RNA that target a particular gene’s messenger RNA (mRNA) — the molecule generated from DNA and used as the template for protein production — to prevent generation of that protein.

A single miRNA can regulate several mRNAs, and a single mRNA can be regulated by multiple miRNAs. miRNAs are known to play important roles in many important cellular processes, including maintaining nerve cell survival and function.

Several studies have shown that dysregulation of miRNAs and other RNA molecules may contribute to neurodegeneration in ALS patients.

Thus, identifying deregulated miRNAs in ALS could serve “as a potential tool for ALS diagnosis, prognosis, and follow-up, or to gain insight into the [disease-associated mechanisms] of the disease,” the researchers wrote.

A team of researchers in Spain set out to identify different miRNAs in 60 ALS patients (52 with sporadic ALS and eight with familial ALS) and 29 age- and sex-matched healthy individuals. Healthy participants were recruited from non-genetically related relatives of ALS participants.

They first analyzed the levels of 185 miRNAs in the blood of seven ALS patients and six healthy controls. Results showed that 13 miRNAs had significantly different levels between the two groups.

The blood levels of these 13 miRNAs were then assessed in two larger, independent groups of participants comprising 53 ALS patients and 23 healthy individuals.

ALS patients had significantly lower levels of miR-335-5p, compared with healthy people. No significant differences were found for the other 12 miRNAs, according to the validation analysis.

The researchers noted that miR-335-5p was previously shown to target the mRNA of more than 2,000 genes, suggesting that changes in its levels could have an impact on multiple cell functions.

They then evaluated whether miR-335-5p deficiency affected key nerve cell features associated with neurodegeneration, including mitochondrial dynamics, oxidative stress levels, and activity of cell death-promoting proteins.

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

These features were assessed in healthy nerve cells grown in the lab in the absence or presence of a molecule that specifically suppresses the activity of miR-335-5p.

Compared with healthy nerve cells, those with induced lower miR-335-5p levels had abnormally shaped mitochondria (which provide cells energy), an increase in mitochondria degradation, and higher levels of oxidative stress-related molecules and cell death-promoting proteins.

These findings highlight that lower levels of miR-335-5p may promote nerve cells’ mitochondria degradation and death, and support “the notion that dysregulation of miRNAs may be involved in the [disease-associated] process of neuron degeneration in ALS,” the researchers wrote.

They noted that motor nerve cells derived from people with spinal muscular atrophy — another motor nerve cell disease — were previously shown to also have lower-than-normal levels of miR-335-5p, suggesting that this miRNA may play a role in degeneration of motor neurons.