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Jul 16

Research Bit:July RNA-based regulation of TDP-43 nuclear export

Research Bits
The Packard Center welcomed Lindsey Hayes, MD, PhD from the Johns Hopkins University to a recent Investigator's meeting.

Date: July 16, 2021

Presenter: Lindsey Hayes, MD, PhD

Talk Title: RNA-based regulation of TDP-43 nuclear export

What was the question being asked?

What are the factors that govern the movement of TDP-43 out of the nucleus?

Why is this important for ALS research?

TDP-43 is a protein that is normally present within the nucleus of cells, although it is constantly shuttling in and out of the nucleus through the nuclear pore. In the motor neurons of many ALS patients (>97%), TDP-43 is observed to be abnormally present within the cytoplasm and absent from the nucleus. This “TDP-43 mislocalization” is considered one of the hallmarks of ALS. Dr. Hayes aims to understand what allows TDP-43 to move in and out of the nucleus in healthy cells. This will subsequently allow her to determine why TDP-43 mislocalization occurs so frequently in the context of ALS.

What was the take-home message?

Using a variety of clever and creative approaches, Dr. Hayes demonstrates that TDP-43, which is normally bound to many other molecules in the nucleus, passively diffuses out when it is not bound to its favorite partner, RNA. RNA acts as a “tether” which is constantly holding it within the nucleus. However, when the RNA is destroyed intentionally in her experiments, Dr. Hayes and her group observed that TDP-43 is no longer anchored in the nucleus and can move out into the cytoplasm.

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

This large body of data significantly improve our fundamental understanding of the factors that govern TDP-43 presence within the nucleus. Future studies will be focused on investigating how ALS may affect this normal regulation of TDP-43, with the end goal of trying to prevent TDP-43 mislocalization from occurring in ALS patients.

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