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May 18

Research Bit: Role of arginine-rich DPRs in nuclear import inhibition

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

Date: May 15, 2020

Presenter: Lindsey Hayes

Talk Title: Role of arginine-rich DPRs in nuclear import inhibition

What was the question being asked?

How do the dipeptide repeat proteins (DPRs) that are produced due to the c9orf72 mutation change how molecules move between the nucleus and the cytoplasm?

Why is this important for ALS research?

Cells depend on constant transport of proteins and other molecules into and out of the nucleus. Many studies have shown that this transport is slower in neurons that have the C9orf72 ALS mutation. However, the reason this happens is unknown. This work serves to understand if and how the DPRs lead to slower transport between the nucleus and cytoplasm, and whether this could contribute to the degeneration of neurons in the context of ALS.

What was the take-home message?

Of the 5 DPRs that are produced by the mutation, only the two that contain arginine (GR and PR) seem to alter nuclear transport. Specifically, these two DPRs reduce the ability of cells to import things into the nucleus. Importantly, GR and PR must be present near the nuclear pore (the gate between the nucleus and cytoplasm) in order to reduce the amount of nuclear import.

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

This project is a rigorous study of how the DPRs can affect the biology of nuclear transport, and investigates the specific parts of transport that are affected. This provides a much more targeted hypothesis about how the DPRs contribute to neuronal degeneration, and allows for future studies to be performed to identify therapies that re-activate nuclear import to reduce neuronal degeneration.

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