Study links missing enzyme to early brain damage in ALS

Researchers using a fish model of amyotrophic lateral sclerosis (ALS) found that damage to the cerebellum — a brain region not traditionally associated with ALS — begins before motor symptoms emerge.

This damage appears to be driven by reduced levels of PAICS, an enzyme involved in the production of molecules needed for DNA maintenance and repair.

The findings suggest PAICS may serve as both a disease biomarker and a potential therapeutic target. Restoring PAICS activity in the ALS model reduced DNA damage and improved motor function.

The data position PAICS “as a therapeutic target and a [disease] biomarker,” while also providing further evidence that ALS affects regions of the brain beyond those directly involved in movement, the researchers wrote. “These findings not only enhance our understanding of ALS as a multisystem disorder but also open new avenues for therapeutic intervention.”

The study, “PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis,” was published in the journal Brain.

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ALS is a neurodegenerative disease marked by the progressive loss of motor neurons, the specialized nerve cells that control movement. As these cells die, patients experience worsening muscle weakness that can affect movement, speech, swallowing, and breathing.

ALS research has focused primarily on the brain and spinal cord regions where motor neurons reside. Recent imaging studies, however, have shown that degeneration extends beyond these regions. Among the affected areas is the cerebellum, a structure at the back of the brain that is best known for coordinating balance and movement.

While scientists have increasingly recognized the cerebellar involvement in ALS, the mechanisms driving that damage remain unclear.

Seeking to better understand the process, researchers in Canada examined cerebellar changes in a zebrafish model of C9orf72-associated ALS. Mutations in the C9orf72 gene are the most common known genetic cause of ALS, accounting for about 40% of familial ALS cases and 7% of sporadic cases. Zebrafish are commonly used for research because they share many genes and biological pathways with humans.

The scientists found that the cerebellum began to degenerate and key cell types died off early in the disease, before any obvious movement problems emerged in the fish.

“Our results show that ALS is not limited to motor regions of the brain,” Kessen Patten, PhD, lead author of the study and professor at the Institut national de la recherche scientifique, said in an institute news story. “Significant changes occur elsewhere, long before symptoms appear, which profoundly changes our understanding of the disease.”

Looking for molecular changes that might explain this early degeneration, the researchers found that affected cerebellar cells showed reduced activity of the paics gene, which encodes the PAICS enzyme. PAICS plays an essential role in producing purines, molecules that serve as building blocks for DNA and help support DNA repair and maintenance. Correspondingly, PAICS protein levels were also reduced.

The findings extended beyond the zebrafish model. Similar reductions in PAICS levels were observed in postmortem cerebellar tissue from people with ALS and in lab-grown motor neurons derived from ALS patients.

“Altogether, these findings indicate that downregulation of PAICS expression is a conserved feature across zebrafish, post-mortem cerebellum and patient-derived motor neurons,” the researchers wrote.

To determine whether PAICS loss could directly contribute to disease, the team genetically engineered healthy zebrafish to lack the paics gene. Those fish developed movement abnormalities similar to those seen in the ALS model and showed signs of cerebellar neuron loss.

The loss of PAICS was associated with increased DNA damage, suggesting that reduced enzyme levels may impair the cells’ ability to repair genetic damage and contribute to cell damage.

When the ALS zebrafish model was instead engineered to have higher paics gene activity, DNA damage was reduced, nerve cells in the cerebellum had better survival, and motor problems were reversed.

The researchers believe that a loss of PAICS in ALS leads to a shortage of the building blocks needed for DNA repair, leaving cerebellar cells vulnerable to accumulating damage.

“This creates a self-perpetuating cycle of unresolved DNA damage …, repair pathway suppression and neurodegeneration,” they wrote.

The team said metabolites that accumulate when PAICS activity is impaired could potentially be measured as biomarkers of ALS diagnosis or disease progression. Still, they noted that more work is needed to understand why the PAICS gene becomes disrupted in ALS and exactly how the resulting DNA damage contributes to neurodegeneration.

Such insights “may provide us with key insights to target specific pathways via small molecules or gene therapy to stop or even reverse the progression of ALS,” they wrote.