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Liquid droplets and hydrogels: protein phase transition in health and disease (360G-Wellcome-203249_Z_16_Z)

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.

£2,568,786

05 Jul 2016

Grant details
Amount Awarded 2568786
Applicant Surname St George-Hyslop
Approval Committee Science Interview Panel
Award Date 2016-07-05T00:00:00+00:00
Financial Year 2015/16
Grant Programme: Title Collaborative Award in Science
Internal ID 203249/Z/16/Z
Lead Applicant Prof Peter St George-Hyslop
Other Applicant(s) Prof Clemens Kaminski, Prof David Klenerman, Prof Gian Gaetano Tartaglia, Prof Michele Vendruscolo, Prof Ole Paulsen, Prof Tuomas Knowles, Dr Gabriele Kaminski, Prof Christine Holt, Prof Kwangwook Cho
Planned Dates: End Date 2021-04-01T00:00:00+00:00
Planned Dates: Start Date 2017-04-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England
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