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Wrong location of a key protein in neuron causes amyotrophic lateral sclerosis

Researchers from the University of California and San Diego School of Medicine found that a key protein TDP-43 plays an important role in pathogenesis of amyotrophic lateral sclerosis (ALS). TDP-43 is responsible for accurate synthesis of ribonucleic acid (RNA), molecules reproducing genetic information from DNA to proteins.

In the cells of healthy humans TDP-43 is located in the nucleus, the container for DNA. But in ALS patients TDP-43 is found in cytoplasm, the cell’s component separating nucleus from the shell. Thus it doesn’t interact with DNA and can’t function properly.

The scientists used a mouse model in the research. They found out that one-third of the genes active in the animal brain are influenced by TDP-43. These genes had a lot of TDP-43 binding sites on very long introns. Intron is the part of DNA which doesn’t code any protein. Usually they are cut out during so called RNA splicing process. The TDP-43 binding sites are necessary for the proper removal of introns.

The researchers speculate that amyotrophic lateral sclerosis affects only central nervous system because of these long introns with TDP-43 binding sites. The genes active in other tissues have much shorter introns and they are less dependent of TDP-43. The scientists suggest that genes affected by the TDP-43 are crucial for normal neuron functioning.

Besides, the researchers discovered that TDP-43 controls its own synthesis. The autoregulation keeps TDP-43 protein levels stable. The protein loss causes more generation of TDP-43, and it is more likely to accumulate in cytoplasm.

The absence of TDP-43 in nucleus and its concurrent accumulation in cytoplasm play role not only in ALS pathogenesis but also in the development of other neurodegenerative diseases. The abnormal TDP-43 is known to be responsible for frontotemporal lobar dementia. This pathology is characterized by progressive changes in personality and behavior. The results of the research may be used to design new therapies and drugs.