Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Liquid droplets and hydrogels: protein phase transition in health and disease

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding £2.6M
Period Apr 2017 — Apr 2021

In plain English

AI plain-English summary

Nerve cells rely on tiny protein droplets that form and dissolve like liquid in water to control how they make proteins at their synapses. The protein FUS normally switches between a dispersed state, a liquid droplet, and a gel-like solid, but harmful mutations can lock it into an irreversible solid form that disrupts these droplets and damages nerve terminals. This matters because the same protein clumps are found in patients with certain forms of motor neuron disease and frontotemporal dementia. Scientists do not yet understand what normally controls FUS’s ability to switch between these states, or how mutations break that control. The team will identify the molecular switches—chemical modifications and partner proteins—that regulate FUS assembly, then use physics and single-molecule imaging to watch how these switches affect droplet behaviour in living neurons. They will also test whether faulty FUS assemblies can be detected in cerebrospinal fluid. This is fundamental science. It will not produce a treatment tomorrow. But understanding how a single protein’s physical state controls protein production at synapses could eventually reveal new targets for drugs that keep these droplets from turning into harmful solids.

View original technical description
We have shown that local control of RNA and protein metabolism by ribonucleoprotein granules plays a vital role in synaptic function. Recently, we discovered that the RNA binding protein, FUS, physiologically transitions between dispersed, liquid droplet and hydrogel states. These transitions, driven by its LC domain, underpin reversible assembly of FUS granules and regulate protein synthesis in nerve terminals. Crucially, pathogenic FUS mutations induce irreversible assembly and RNP granule dysfunction. Our results raise questions about how FUS assembly is regulated, how it affects synaptic activity, and causes disease. To address these questions, we will use bioinformatics, proteomics, and iCLIP to identify key modulators (posttranslational modifications, interacting proteins) (Aim 1). We will use soft matter physics to investigate their impact on FUS assembly (Aim 2). We will apply advanced single molecule imaging tools to assess how modulators affect granule function (Aim 3). We will explore the reciprocal relationships between FUS assembly and synaptic activity in neurons under optogenetic control (Aim 4). We will use novel imaging methods to determine whether FUS assemblies are secreted and can be detected in CSF (Aim 5). This work has major implications for neurobiology and medicine.

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Researchers

Peter St George-Hyslop (EPMC Awardee)

Related Research

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Original classification

Collaborative Award in Science

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