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Jun 15
2020

Research Bit: Toxicity and Production of poly(GR) in C9ORF72-ALS/FTD

Research Bits
The Packard Center welcomed Fen-Biao Gao from the University of Massachucetts Medical School to a recent Investigator's meeting

Date: June 12, 2020

Presenter: Fen-Biao Gao, PhD

Talk Title: Toxicity and Production of poly(GR) in C9ORF72-ALS/FTD

What was the question being asked?

Since the C9ORF72 mutation leads to the production of 5 different toxic di-peptide repeats, which ones contribute to the degeneration of motor neurons, and how does this happen in vivo?

Why is this important for ALS research?

The C9ORF72 ALS mutation can lead to the production of toxic RNA and dipeptide repeats, which makes it difficult to parse out what causes the degeneration of neurons in patients.

What was the take-home message?

Poly(GR) leads to increased DNA damage in fly models, which leads to activation of p53 activity, which functions to defend the cell from the negative effects of DNA damage. However, when the DNA damage persists over long periods of time, this can lead to the programmed death of the cell, which may explain why neurons are dying in ALS patients.

It has been shown by many labs that poly(GR) and poly(PR) reduce the production of new proteins in the cell. This work identifies a structural explanation for this. GR and PR fit into a specific part of the ribosome, which prevents the ribosome from adding new peptides to the protein it is trying to make.

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

Now that we understand how the GR and PR peptides disrupt the function of ribosomes, there can be focused development of therapies that prevent this form of toxicity.

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