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PhaseAge SIGNED

The chemistry and physics of RNP granules: how they form, age and cause disease

Total Cost €

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EC-Contrib. €

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Partnership

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Project "PhaseAge" data sheet

The following table provides information about the project.

Coordinator
TECHNISCHE UNIVERSITAET DRESDEN 

Organization address
address: HELMHOLTZSTRASSE 10
city: DRESDEN
postcode: 1069
website: http://www.tu-dresden.de/

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Germany [DE]
 Project website http://n.a.
 Total cost 1˙931˙303 €
 EC max contribution 1˙931˙303 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2016-COG
 Funding Scheme ERC-COG
 Starting year 2017
 Duration (year-month-day) from 2017-04-01   to  2022-03-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    TECHNISCHE UNIVERSITAET DRESDEN DE (DRESDEN) coordinator 1˙284˙801.00
2    MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV DE (MUENCHEN) participant 646˙501.00

Map

 Project objective

Recent studies suggest that defective ribonucleoprotein (RNP) granules and altered RNA processing cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, defective RNP granules only develop late in life, suggesting that young cells have mechanisms in place to prevent their formation. We recently demonstrated that physiological RNP granules form through phase separation in the cytoplasm and adopt a liquid-like state, but with time transition into an aberrant disease-associated state with solid material properties. Focussing on this conceptual advance, we will

1) investigate the molecular mechanisms of RNP granule formation; 2) pinpoint the molecular events that lead to aberrant RNPs, focusing on disease-associated mutations, changes in environmental conditions, post-translational modifications and molecules with fluidizing or solidifying effects; and 3) define the mechanisms of RNP quality control, which prevent aberrant phase transitions or reverse RNP aggregates to their normal state, thus rescuing a cell from an otherwise fatal condition.

Key to the project are recently developed methodologies to reconstitute RNPs from purified proteins and RNAs, and biophysical techniques to analyse the material properties of RNP granules. Combined with our ability to perform time-resolved studies of RNPs in living cells and our thematic focus on the link between RNP dynamics and functionality, this project represents a systematic and realistic approach to tackling the essential question of how RNP granules form and why they cause disease.

We expect that our findings will have impact far beyond ALS and FTD, because aberrant phase transitions may be at the heart of many protein-misfolding diseases. We envision that our findings will lead to new therapeutic interventions that may significantly improve the prospects of patients afflicted with these diseases.

 Publications

year authors and title journal last update
List of publications.
2019 Jessica Mandrioli, Laura Mediani, Simon Alberti, Serena Carra
ALS and FTD: Where RNA metabolism meets protein quality control
published pages: , ISSN: 1084-9521, DOI: 10.1016/j.semcdb.2019.06.003
Seminars in Cell & Developmental Biology 2019-10-31
2019 Titus M. Franzmann, Simon Alberti
Prion-like low-complexity sequences: Key regulators of protein solubility and phase behavior
published pages: 7128-7136, ISSN: 0021-9258, DOI: 10.1074/jbc.tm118.001190
Journal of Biological Chemistry 294/18 2019-10-31
2018 Simon Alberti, Shambaditya Saha, Jeffrey B. Woodruff, Titus M. Franzmann, Jie Wang, Anthony A. Hyman
A User’s Guide for Phase Separation Assays with Purified Proteins
published pages: 4806-4820, ISSN: 0022-2836, DOI: 10.1016/j.jmb.2018.06.038
Journal of Molecular Biology 430/23 2019-10-31
2019 Simon Alberti, Amy Gladfelter, Tanja Mittag
Considerations and Challenges in Studying Liquid-Liquid Phase Separation and Biomolecular Condensates
published pages: 419-434, ISSN: 0092-8674, DOI: 10.1016/j.cell.2018.12.035
Cell 176/3 2019-10-31
2019 Simon Alberti, Dorothee Dormann
Liquid–Liquid Phase Separation in Disease
published pages: , ISSN: 0066-4197, DOI: 10.1146/annurev-genet-112618-043527
Annual Review of Genetics 53/1 2019-10-31
2019 Laura Mediani, Jordina Guillén‐Boixet, Jonathan Vinet, Titus M Franzmann, Ilaria Bigi, Daniel Mateju, Arianna D Carrà, Federica F Morelli, Tatiana Tiago, Ina Poser, Simon Alberti, Serena Carra
Defective ribosomal products challenge nuclear function by impairing nuclear condensate dynamics and immobilizing ubiquitin
published pages: , ISSN: 0261-4189, DOI: 10.15252/embj.2018101341
The EMBO Journal 38/15 2019-10-31
2019 Lara Marrone, Hannes C. A. Drexler, Jie Wang, Priyanka Tripathi, Tania Distler, Patrick Heisterkamp, Eric Nathaniel Anderson, Sukhleen Kour, Anastasia Moraiti, Shovamayee Maharana, Rajat Bhatnagar, T. Grant Belgard, Vadreenath Tripathy, Norman Kalmbach, Zohreh Hosseinzadeh, Valeria Crippa, Masin Abo-Rady, Florian Wegner, Angelo Poletti, Dirk Troost, Eleonora Aronica, Volker Busskamp, Joachim Weis,
FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy
published pages: 67-84, ISSN: 0001-6322, DOI: 10.1007/s00401-019-01998-x
Acta Neuropathologica 138/1 2019-10-31
2018 Simon Alberti, Serena Carra
Quality Control of Membraneless Organelles
published pages: 4711-4729, ISSN: 0022-2836, DOI: 10.1016/j.jmb.2018.05.013
Journal of Molecular Biology 430/23 2019-10-31
2018 Jie Wang, Jeong-Mo Choi, Alex S. Holehouse, Hyun O. Lee, Xiaojie Zhang, Marcus Jahnel, Shovamayee Maharana, Régis Lemaitre, Andrei Pozniakovsky, David Drechsel, Ina Poser, Rohit V. Pappu, Simon Alberti, Anthony A. Hyman
A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins
published pages: 688-699.e16, ISSN: 0092-8674, DOI: 10.1016/j.cell.2018.06.006
Cell 174/3 2019-08-07
2018 Shovamayee Maharana, Jie Wang, Dimitrios K. Papadopoulos, Doris Richter, Andrey Pozniakovsky, Ina Poser, Marc Bickle, Sandra Rizk, Jordina Guillén-Boixet, Titus M. Franzmann, Marcus Jahnel, Lara Marrone, Young-Tae Chang, Jared Sterneckert, Pavel Tomancak, Anthony A. Hyman, Simon Alberti
RNA buffers the phase separation behavior of prion-like RNA binding proteins
published pages: 918-921, ISSN: 0036-8075, DOI: 10.1126/science.aar7366
Science 360/6391 2019-08-07

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