Loss of Enzyme May Contribute to Motor Neuron Death in ALS, Study Shows

The loss of a key enzyme, called adenosine deaminase, in astrocytes ­­­­— the energy-supporting cells of neurons ­­­­— leads to a toxic accumulation of molecules that contributes to the death of motor neurons seen in amyotrophic lateral sclerosis (ALS), a study shows.

The study, “Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis,” was published in the journal Brain.

Several genes have been associated with the inherited form of ALS, but in up to 10% of all ALS cases, the disease is linked to a mutation called hexanucleotide repeat expansion (HRE) in the C9orf72 gene. This type of mutation is also seen in patients with frontotemporal dementia (FTD).

Previous studies have shown that mutations in the C9orf72 gene lead to an imbalance in the metabolism of fats (lipids) in motor neurons, supporting evidence that an imbalance in energy and lipid metabolism could be particularly relevant to ALS.

Astrocytes, a group of star-shaped glial cells (the most abundant cell types in the central nervous system), provide neurons with energy and work as a platform to clean up their waste.

While the loss of motor neurons is key in ALS development, growing evidence suggests that the malfunction of astrocytes may play a role in disease progression by secreting toxic proteins or inflammatory molecules that induce the death of motor nerve cells, among other processes.

Researchers sought to investigate if and how the C9orf72-HRE mutation affects astrocytes’ energy production and motor neuron death. They used both fibroblasts (skin cells) and astrocytes derived from induced neural progenitor cells (iNPCs) from ALS patients (six positive for C9orf72-HRE and three with sporadic ALS) and eight matched controls. Participants’ metabolisms were profiled to identify potentially deficient metabolic pathways.

The analysis showed that the levels of an enzyme called adenosine deaminase — vital for the normal metabolism of cells ­­­­— were reduced in fibroblasts in iNPC-derived induced astrocytes, and in induced neurons from patients with the C9orf72 mutation and sporadic ALS.

Moreover, the lack of the enzyme turned the patient-derived induced astrocytes metabolically abnormal (they accumulated toxic amounts of adenosine), causing 60% to 80% in cell loss. When researchers inhibited the enzyme in the healthy astrocytes, they saw the same adenosine accumulation. When growing these astrocytes together with motor neurons in the lab, researchers saw an increased toxicity to the motor cells.

Adenosine deaminase works by breaking down metabolites, called adenosine and deoxyadenosine, into inosine and deoxyinosine. Researchers saw that the addition of inosine to astrocytes ­­­­— a strategy that bypasses the need for the enzyme ­­­­— corrected the cells’ metabolic imbalances and led to increased survival of motor neurons when they were co-cultured together.

These findings suggest that “inosine supplementation, in combination with modulation of the level of adenosine deaminase may represent a beneficial therapeutic approach to evaluate in patients with amyotrophic lateral sclerosis,” the researchers wrote.

What triggers the loss of adenosine deaminase and at what stage this occurs in ALS patients remain unknown, but “work is underway in our laboratory to further investigate the role of ADA in ALS,” they stated.