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Apr 16

Research Bit: Crosstalk between proteostasis and nuclear transport in C9

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

Date: April 16, 2021

Presenter: Thomas Lloyd, MD, PhD

Talk Title: Crosstalk between proteostasis and nuclear transport in C9

What was the question being asked?

How do various affected cellular pathways (nucleocytoplasmic transport and endoplasmic reticulum maintenance) contribute to altered protein homeostasis in motor neurons affected by ALS?

Why is this important for ALS research?

Altered proteostasis, or the process by which the correct amount and types of protein or maintained in cells, is one of the main hypotheses regarding how ALS leads to neuronal death. Dr. Lloyd’s lab uses fruit flies as a model for neurodegeneration by pumping them full of the various RNA proteins that cause ALS, such as the dipeptide repeat proteins that are generated as a result of the C9orf72 mutation. Thus, they are able to study how neurons and related cells in these flies respond, and make predictions to design more targeted experiments in human neurons.

What was the take-home message?

They observe that lysosomes, one of the main “garbage disposal” components of the cell, are less functional in cells with the C9orf72 mutation. Importantly, this occurs following dysfunction in the nuclear pore complex, which has been characterized by the Lloyd and other labs. Additionally, they report alterations in the function of the endoplasmic reticulum (ER) in this same fruit fly model. The ER is a network of tubules and sheets that runs throughout each cell, including within the axons of neurons. Changes in the fluidity of the ER in neurons with the C9orf72 mutation may be linked to altered transport of materials throughout axons.

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

Part of the presented work investigates some of the subsequent problems that arise once nuclear transport is dysfunctional, while the rest focuses on the distal part of neurons (axons). Together, this work may provide insight into the extent to which nucleocytoplasmic transport defects alter biology in the rest of the cell.

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