TDP-43 Accumulation Causes RNA Instability in Nerve Cells of ALS Patients

The accumulation of TDP-43, a widely expressed nuclear protein that binds both DNA and RNA, causes RNA instability in nerve cells derived from patients with amyotrophic lateral sclerosis (ALS). That leads to disruption of energy and protein production, and eventually causes cells’ death.

Those findings were described in the study, “Abnormal RNA stability in amyotrophic lateral sclerosis,” published in Nature Communications.

ALS is a progressive neurological disorder in which motor neurons — the nerve cells responsible for controlling voluntary muscles — gradually degenerate and die, causing muscles to shrink (atrophy) and become weaker.

Frontotemporal dementia (FTD) comprises a group of neurological disorders that affect the frontal and temporal lobes of the brain, which are the regions typically associated with personality, behavior and language.

Patients with FTD can experience a wide array of symptoms, ranging from dramatic changes in personality to losing their ability to speak.

Almost half of the patients diagnosed with ALS experience serious cognitive changes, such as impulsive behavior and language deficits, similar to those found in subjects with FTD. In addition, ALS and FTD share another common key feature: the abnormal accumulation of TDP-43 (transitive response DNA/RNA-binding protein 43 kDa), a protein that normally binds and stabilizes RNA, inside nerve cells.

Genes, which are composed of DNA sequences, are transcribed into molecules called RNA. In turn, RNA molecules are used as templates to make proteins, which carry out various functions in a cell.

Although previous studies already demonstrated there is an abnormal amount of RNA in disease models of ALS and FTD, so far researchers still do not know if this due to an impairment in the production or degradation of RNA molecules.

So, to understand if and how RNA stability could be affected in these disorders, investigators used Bru-seq and BruChase-seq — two innovative techniques that allow researchers to analyze the production and stability of RNA molecules — in cells derived from patients with ALS.

With this approach, they found severe abnormalities in the stability of RNA molecules encoding components of signaling pathways involved in the production of energy (mitochondrial RNA) and proteins (ribosomal RNA).

Remarkably, they observed the same trend after forcing cells to produce an excessive amount of an artificial form of TDP-43, suggesting that this RNA-binding protein has a role in RNA destabilization. These findings also held true when researchers analyzed postmortem samples from patients with ALS and FTD.

Altogether, these observations suggest that the accumulation of TDP-43 in nerve cells promotes RNA instability, which can distress important mechanisms involved in the production of energy and proteins,  ultimately leading to cell’s death.

Now, researchers hope these findings can be used to help generate novel therapeutic strategies to restore RNA stability in these disorders.

“Together with our observations, these data attest to the promise of therapeutic strategies aimed at restoring RNA homeostasis by preventing RBP [RNA-binding proteins] sequestration, disruption of RNA granules, and consequent RNA instability. We expect that such strategies, if successful, will not only improve RNA homeostasis [equilibrium], but also prevent the neuron loss and protein deposition that are hallmarks of ALS, FTD and related neurodegenerative disorders,” the authors wrote.