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Sep 10

Research Bit: The RNA binding specificity and phase separation interactome of FUS – Implications for function and disease

Research Bits
The Packard Center welcomed Marc-David Reupp from Kings College London to a recent Investigator's meeting.

Date: September 10, 2021

Presenter: Marc-David Reupp, PhD

Talk Title: The RNA binding specificity and phase separation interactome of FUS – Implications for function and disease

What was the question being asked?

Recent in vivo models suggest FUS-linked ALS leads to a toxic gain of function, but the functions and targets of the FUS protein remain unclear. The Ruepp lab is focused on gaining insight into the role of this protein in neurodegeneration as well as the consequences of ALS-linked FUS on RNA metabolism.

Why is this important for ALS research?

While only 5% of ALS cases have a genetic cause, 25 genes have been identified that are associated with the disease. Novel FUS mutations are the most frequent cause of juvenile onset ALS in Germany and China. The FUS gene codes for the FUS protein, which is a highly-conserved, multi-functional DNA/RNA binding protein involved in gene expression. It is mainly nuclear in steady-state but can shuttle in between the nucleus and cytoplasm. Most mutations lead to an almost complete exclusion of FUS from the nucleus.

What was the take-home message?

Splices and defects are not just an issue with Spinal Muscular Atrophy (SMA) and FUS-linked ALS but a common characteristic among neurodegenerative diseases. It remains unclear if splicing and defects are an initial cause for motor neuron death or an already stressed cell. Future research is needed across genes, mutations, and diseases to understand the context of RNA-binding proteins. In addition, phase separation affects splicing, chromatin association, DNA damage repair, and mitochondria, but it is not a prerequisite for toxicity. Future work is needed to gain insight into how phase separation dependent and independent interactomes can be translated to other RNA-binding proteins that phase separate but controls are necessary to ensure the factors are not an artifact.

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

A shared mechanism between ALS and another neurodegenerative disease indicates the significance of the biological mechanism and how it can be used as therapeutic target.


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