RNA Processing Defect Causes Motor Neuron Death

Impairment of the RNA processing pathway in motor neurons is responsible for their death in Lou Gehrig’s disease.

AsianScientist (Jan. 5, 2018) – Scientists in Japan have gained a better understanding of the molecular mechanism behind neuronal cell death in amyotrophic lateral sclerosis (ALS). Their findings are published in the journal PLOS One.

ALS, also known as Lou Gehrig’s disease, is a fatal neurological disease that causes the death of motor neurons that control muscles in the body. There are currently no radical treatments for ALS, and the average survival after diagnosis is two to four years. Named after an American baseball player who had ALS, the condition gained attention after a series of videos known as the Ice Bucket Challenge went viral on the internet in 2014.

Depletion of a protein called TDP-43 has been previously linked to the death of motor neurons, leading to ALS. TDP-43 plays a role in processing RNA molecules in cells, but its exact function remains unclear.

In this study, a team of scientists led by Dr. Masao Yahara of Hokkaido University in Japan decided to investigate the relationship between TDP-43 and mRNA processing to understand exactly how the depletion of TDP-43 leads to cell death and ALS. The team knocked down the gene coding for TDP-43 in neuroblastoma, a cultured cell line, which reduced the protein levels of TDP-43, resulting in cell death. However, the effect was not immediate. There was a time lag, which meant that TDP-43 does not affect cell death directly, but that several cascading processes are involved.

The researchers thus focused on small nuclear RNAs (snRNAs), which also play a role in the processing of RNA and are essential for cell survival. The researchers found that knocking down TDP-43 decreased only one type of snRNA, called U6, but did not affect other types of snRNA. This suggested that the reduction in U6 snRNA was involved in the death of cells. When they added U6 snRNA back to the TDP-43 depleted cells, it rescued the cells from death.

The researchers found that TDP-43 binds to U6 snRNA, apparently stabilizing the U6 snRNA molecules. The team speculates that when TDP-43 is depleted, U6 snRNA is released, becomes unstable and degrades. This may lead to the death of neurons and the propagation of ALS.

However, they also found that U6 snRNA only had a limited ability to restore defects in RNA processing in TDP-43 depleted cells. This implied that U6 snRNA activated an unknown pathway to save neurons from death.

“We demonstrated that U6 snRNA, regulated by TDP-43, plays an important role in maintaining motor neurons, but its mechanism is still shrouded in mystery. Further investigation could potentially lead to ways to slow or stop neuronal cell death and thus treat ALS patients,” said Professor Masataka Kinjo of Hokkaido University who is a co-author of the study.

The article can be found at: Yahara et al. (2017) U6 snRNA Expression Prevents Toxicity in TDP-43-knockdown Cells.


Source: Hokkaido University; Photo: Shutterstock.
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