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Aug 14
2020

Research Bit: Nuclear pore complex quality control in C9orf72 ALS/FTD

Research Bits
The Packard Center welcomed Alyssa Coyne, PHD from Johns Hopkins University to a recent Investigator's meeting.

Date: August 14, 2020

Presenter: Alyssa Coyne, PhD

Talk Title: Nuclear pore complex quality control in C9orf72 ALS/FTD

What was the question being asked?

Why does the nuclear pore complex become broken in the motor neurons of patients with C9orf72 ALS/FTD?

Why is this important for ALS research?

The nuclear pore complex (NPC) acts as a gate between the two main compartments within cells (the nucleus and cytoplasm). The NPC is a big grouping of proteins that forms a channel within the nucleus, and proteins within the NPC work to make sure that only specific molecules move into and out of the nucleus. Many studies have shown that the ALS-linked C9orf72 mutation directly leads to loss in the ability of nuclei in motor neurons to control passage between the nucleus and cytoplasm. Recently, Dr. Coyne published a precise assessment of the NPC components that are absent in diseased neurons, which subsequently leads to an issue in transport between the nucleus and cytoplasm. The outstanding question is why the NPC is missing these components in these diseased neurons. Dr. Coyne has identified a specific protein that is involved in normal degradation of nuclear pore proteins, and has additionally shown that this protein is hyperactive in diseased neurons. This directly leads to increased degradation of its target proteins within the NPC, providing an explanation for the broken NPC observed in neurons with the C9orf72 ALS mutation.

What was the take-home message?

In diseased neurons, this protein does not leave the nucleus as it normally should, which leads to significant breakdown of nuclear pore proteins. This leads to many known issues downstream, and provides a potential therapeutic target to prevent the degeneration of motor neurons in patients with the C9ORF72 ALS mutation.

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

This study presents a blend of disease-based experiments and fundamental biology. It provides solid evidence for a therapeutic target, as well as demonstrates the importance of understanding the biology involved in disease before trying to assess whether that biology is altered by disease.

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