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Disrupted RNA transportation results in neurodegeneration

Researchers report that reduced TDP-43 expression disrupts axonal transport of messenger RNAs to cause neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).

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According to researchers, disruptions to RNA transportation within neurons causes two common neurodegenerative diseases; amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, and frontotemporal lobar degeneration (FTLD).

In their paper, scientists from Osaka University and National Center of Neurology and Psychiatry, both Japanese, report that reduced transportation of RNA by the protein TDP-43 causes the build up of aggregates, disrupting neuronal function and results in ALS and FTLD.

Figure 1 Model of ALS/FTLD pathology associated with abnormal deposition of TDP-43 [credit: National Center of Neurology and Psychiatry].

Figure 1 Model of ALS/FTLD pathology associated with abnormal deposition of TDP-43 [credit: National Center of Neurology and Psychiatry].

The team said they focused their research on what TDP-43 normally does because one of the biggest physiological changes in both ALS and FTLD is the disappearance of TDP-43 from the nucleoli of neurons. TDP-43 is known to bind to RNA and in their first experiment the team showed that in neurons it attaches to messenger RNA (mRNA) that codes for pieces of ribosomes (the structures which translate RNA into protein within cells).

“We discovered TDP-43 in axons and that it binds to ribosomal protein messenger RNA,” explained study first author Seiichi Nagano. “That was strong support for the idea that TDP-43 carries the RNA to the axon where it can be used to make ribosomal proteins. This would allow local synthesis of proteins at ribosomes built in axons.” Their hypothesis was confirmed in their later experiments which showed that when TDP-43 was missing, the mRNA could not be transported to the axon.

The team also examined how axonal growth is altered in cell cultures and mouse embryos when the TDP-43 was missing. They found that in both cases, axon extension and outgrowth were stunted, but that this effect could be overcome by forcing the neurons to overproduce ribosomal proteins.

Figure 2 ibosomal protein mRNA partially reversed impaired axonal outgrowth found in TDP-43-knockdown (KD) neurons. Decrease of TDP-43 in mouse cortical neurons impaired axonal outgrowth, which was significantly improved by overexpression of individual ribosomal protein mRNAs [credit: National Center of Neurology and Psychiatry].

Figure 2 Ribosomal protein mRNA partially reversed impaired axonal outgrowth found in TDP-43-knockdown (KD) neurons.
Decrease of TDP-43 in mouse cortical neurons impaired axonal outgrowth, which was significantly improved by overexpression of individual ribosomal protein mRNAs [credit: National Center of Neurology and Psychiatry].

“Now that we understand TDP-43’s role in transporting the ribosomal protein messenger RNA, it should help us develop new strategies and new targets for ALS and FTLD treatments,” said co-author of the study Dr Hideki Mochizuki. “Our results in reversing stunted axon extension in mouse embryos is promising but is just a first step.”

The study was published in Acta Neuropathologica.

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