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Aug 13
2021

Research Bit: Functional Validation of TDP-43 splicing repression for ALS-FTD

Research Bits
The Packard Center welcomed Phillip Wong from Johns Hopkins University to a recent Investigator's meeting

Date: August 13, 2021

Presenter: Phillip Wong, PhD

Talk Title: Functional Validation of TDP-43 splicing repression for ALS-FTD

What was the question being asked?

Is loss of TDP-43 splicing-repression activity a significant contributor to neuronal degeneration in ALS?

Why is this important for ALS research?

TDP-43 is a protein that is normally present within the nucleus. However, a majority of ALS patients present some motor neurons that no longer have nuclear TDP-43. This means that TDP-43 is no longer able to perform its role in repressing the expression of “cryptic exons”. This function is similar to a librarian hushing loud children during story time. But if the librarian is on an extended lunch break, too many loud kids run rampant through the library. Dr. Wong’s group hopes to use a “substitute” librarian to trick ALS-affected neurons into thinking that TDP-43 is still functioning, which may prevent some of the downstream issues that result from TDP-43 mislocalization.

What was the take-home message?

Using a clever method by which they combine regions of multiple different proteins, Dr. Wong’s group was able to effectively restore TDP-43 function in cells that no longer express the normal protein. Additionally, they show that this rescues some of the deficits that result from lost TDP-43 function, demonstrating that this splicing repression function of TDP-43 is a significant contributor to neuronal degeneration, at least in cell culture.

How do you think the results of this study might impact future approaches to the treatment of ALS?

With this careful work that demonstrates splicing repression of TDP-43 as a strong contributor to neuronal degeneration in cell culture, the door is open to test Dr. Wong’s protein-fusion method in mouse models of ALS. Ultimately, this work will allow for the development of more targeted therapies that focus on restoring TDP-43 to the nucleus, or at least allowing TDP-43 to continue repressing cryptic exon expression.

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