TDP-43 Protein Abnormalities in ALS Linked to DNA Damage

Marisa Wexler MS avatar

by Marisa Wexler MS |

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DNA damage and ALS

Abnormalities in the activity of the protein TDP-43, whose gene is often mutated in amyotrophic lateral sclerosis (ALS), can increase DNA damage in cells, a study shows.

These findings shed light on the molecular underpinnings of ALS, and may open new avenues for treatment, its researchers said.

The study, “TDP-43 mutations link Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage,” was published in PLOS Genetics.

The exact biological mechanisms that cause ALS are not understood. One molecular feature common to both familial and sporadic ALS is the abnormal function of the protein TDP-43.

TDP-43 is usually located in the nucleus — the cellular compartment that houses DNA — where it is involved in DNA and RNA processing. In ALS, however, TDP-43 tends to accumulate in aggregates (clumps) outside of the nucleus in the cytoplasm.

This TDP-43 aggregation is believed to be an important driver of disease in ALS, but its exact consequences are still being worked out.

Researchers with the University of Seville in Spain and the University of Pavia in Italy now demonstrate that, when TDP-43 is not in the nucleus, cells are more vulnerable to DNA damage. Specifically, the scientists showed that cells without nuclear TDP-43 have increased amounts of what is known as R-loops.

DNA in the nucleus normally exists as two antiparallel strands — the basis for its well-known double-helix shape. When DNA is “read” to produce messenger RNA — an intermediate molecule with instructions for protein production — the two strands unwind, so that messenger RNA is essentially built between them. The resulting structure, composed of two DNA strands and one RNA strand, is called an R-loop.

Although R-loops are a normal part of cellular activities, their physical structure is known to make DNA more susceptible to damage. The researchers consistently found that the TDP-43 protein localizes near these R-loops, and potentially participates in the generation of functional RNA molecules.

However, an increase in R-loops in cells lacking nuclear TDP-43, as seen when TDP-43 accumulates in the cytoplasm, resulted in greater DNA damage. The researchers found similar results in several cellular models, including neuronal cell lines and cell lines derived from ALS patients.

“Nuclear depletion of TDP-43 … causes a significant increase in harmful R-loops that leads to DNA breaks,” the researchers wrote.

Because DNA damage is known to degrade cellular health, these findings indicate a link between abnormal TDP-43 function and cell damage.

“It is becoming clear that impaired RNA regulation and processing is a central feature in ALS pathogenesis [development],” they  added. “Our study, reinforces the need of understanding the specific role of ALS in RNA metabolism.”

Targeting this abnormal genetic activity, the team concluded, “is an attractive therapeutic strategy, that could be considered in the future for the treatment of ALS and other neurodegenerative diseases.”