TDP-43 is one of a number of proteins that can misfold in ways that cause neurodegeneration, either via aggregation into solid deposits, or via a diminished amount of functional protein in critical cells in the brain. Research into TDP-43 is at an earlier stage than is the case for amyloid-β, α-synuclein, or other better known proteins that exhibit these problems. Important and quite fundamental discoveries related to the way in which TDP-43 causes pathology are still being made, as is the case in this recently announced paper.
Two common neurodegenerative diseases – ALS and frontotemporal lobar degeneration, or FTLD – result from reduced transportation of RNA by the protein TDP-43, which ultimately disrupts neuron function. Because one of the biggest physiological changes in both ALS and FTLD is the disappearance of TDP-43 from the nucleoli of neurons, the team focused their research on finding out what TDP-43 normally does. TDP-43 is known to bind to RNA, and the team’s first experiment showed that in neurons, TDP-43 attaches to RNA that codes for pieces of ribosomes, which are necessary for making proteins from RNA code.
“We discovered TDP-43 in axons and that it binds to ribosomal protein messenger RNA. 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.” Indeed, further experiments confirmed that hypothesis and showed that when TDP-43 was missing, the RNA in question could not be transported to the axon.
But what happens if the RNA cannot be transported? The researchers examined axon growth in culture as well as in mouse embryos. They found that in both cases, axon extension and outgrowth were stunted when TDP-43 was missing. However, outgrowth could be restored by forcing the neurons to overproduce ribosomal proteins. “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. Our results in reversing stunted axon extension in mouse embryos is promising, but is just a first step.”