RNA-protein interaction; RNA metabolism; FUS; neurodegeneration; miRNA biogenesis; pre-mRNA splicing; genome stability; amyotrophic lateral sclerosis; transgenic mouse model; NMR; ALS; TLS
Loughlin Fionna E., Lukavsky Peter J., Kazeeva Tamara, Reber Stefan, Hock Eva-Maria, Colombo Martino, Von Schroetter Christine, Pauli Phillip, Cléry Antoine, Mühlemann Oliver, Polymenidou Magdalini, Ruepp Marc-David, Allain Frédéric H.-T. (2018), The Solution Structure of FUS Bound to RNA Reveals a Bipartite Mode of RNA Recognition with Both Sequence and Shape Specificity, in Molecular Cell
, 73, 1-15.
Reber Stefan, Stettler Jolanda, Filosa Giuseppe, Colombo Martino, Jutzi Daniel, Lenzken Silvia, Schweingruber Christoph, Bruggmann Remy, Bachi Angela, Barabino Silvia, Mühlemann Oliver, Ruepp Marc-David (2016), Minor intron splicing is regulated by FUS and affected by ALS-associated FUS mutants, in EMBO Journal
, 35(14), 1504-1521.
Nizzardo Monica, Simone Chiara, Salani Sabrina, Ruepp Marc David, Rizzo Federica, Ruggieri Margherita, Zanetta Chiara, Brajkovic Simona, Moulton Hong M., Muehlemann Oliver, Bresólin Nereo, Comi Giacomo Pietro, Corti Stefania (2014), Effect of combined systemic and local morpholino treatment on the spinal muscular atrophy δ7 mouse model phenotype, in Clinical Therapeutics
, 36(3), 340-356.
Lenzken Silvia Carolina, Achsel Tilmann, Carri Maria Teresa, Barabino Silvia ML (2014), Neuronal RNA-binding proteins in health and disease, in WIREs RNA
, 5(4), 565.
Neumann M (2013), Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: Molecular similarities and differences., in Revue neurologique
, 169(10), 793-798.
Lukavsky Peter J., Daujotyte Dalia, Tollervey James R., Ule Jernej, Stuani Cristiana, Buratti Emanuele, Baralle Francisco E., Damberger Fred F., Allain Frederic H-T (2013), Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43, in NATURE STRUCTURAL & MOLECULAR BIOLOGY
, 20(12), 1443-1449.
Vivarelli Silvia, Lenzken Silvia, Ruepp Marc-David, Ranzini Francesco, Maffioletti Andrea, Alvarez Reinaldo, Mühlemann Oliver, Barabino Silvia (2013), Paraquat Modulates Alternative Pre-mRNA Splicing by Modifying the Intracellular Distribution of SRPK2, in PLoS one
, 8(4), e61980.
Waibel Stefan, Neumann Manuela, Rosenbohm Angela, Birve Anna, Volk Alexander E., Weishaupt Jochen H., Meyer Thomas P H, Müller Ulrich F., Andersen Peter M., Ludolph Albert Christian (2013), Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: A clinico-genetic study in Germany, in European Journal of Neurology
, 20(3), 540-546.
Rademakers R., Neumann M., Mackenzie I. R. (2012), Advances in understanding the molecular basis of frontotemporal dementia, in Nat Rev Neurol
, 8, 423-34.
Halliday G., Bigio E. H., Cairns N. J., Neumann M., Mackenzie I. R., Mann D. M. (2012), Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects, in Acta Neuropathol
, 124, 373-82.
Jack Thomas, Simonin Jonathan, Ruepp Marc-David, Thompson Andrew J, Gertsch Jürg, Lochner Martin, Characterizing new fluorescent tools for studying 5-HT3 receptor pharmacology, in Neuropharmacology
, 90, 63.
Mutations in proteins with roles in RNA metabolism are implicated in a wide variety of neurodegenerative diseases, but the pathogenic mechanisms leading to these disorders are not well understood. For example, mutations in the FUS gene (fused in sarcoma; also known as translated in liposarcoma, TLS), which encodes an RNA-binding protein of the hnRNP family, have recently been identified in patients with an inherited form of amyotrophic lateral sclerosis (ALS). Most of these mutations destroy the nuclear localization signal (NLS) of the normally predominantly nuclear FUS protein, leading to cytoplasmic accumulation of FUS aggregates in neurons and glial cells of these ALS patients. Moreover, FUS positive inclusions are also the characteristic hallmark lesions in a subset of patients with frontotemporal lobar degeneration. It is currently unclear if the FUS mutations-associated form of ALS develops due to a gain-of-function of the mutated protein (i.e. toxicity of the cytoplasmatic FUS aggregates), due to a loss-of-function (i.e. inhibition of FUS’ nuclear function), or due to a combination of both. In this Sinergia project, we propose to test the loss-of-function hypothesis. To this end, we want to elucidate the biological function of FUS, which so far is not well understood.FUS is a ubiquitously expressed protein with several structural motifs in the C-terminal half that appear to be involved in nucleic acid binding. Consistent with this, FUS has been implicated in a variety of cellular processes linked to RNA metabolism, miRNA maturation, and DNA repair. With an interdisciplinary team of experts in both RNA biology (F. Allain, S. Barabino, O. Mühlemann) and molecular pathology of neurodegenerative disorders (M. Neumann), and with a broad spectrum of methods, comprising structural biology, biochemistry, molecular and cell biology, and transgenic mouse models, we plan to i) identify genome-wide the RNAs and proteins interacting with FUS, ii) determine the structural basis for the specificity of these interactions, iii) understand the molecular role of FUS in selective miRNA maturation, regulation of alternative splicing, and DNA damage response, and iv) find out how a failure in any of these potential functions of FUS can lead to neurodegeneration and specifically to death of motor neurons.The results of our research are expected to not only reveal the molecular mechanism leading to FUS-associated ALS and FTLD, but generally to provide significant new insight into the emerging connection between misregulation of RNA metabolism and neurodegeneration, a connection that is currently implied in a variety of addiditional neurological diseases, including spinocerebellar ataxia 2 (SCA-2), spinal muscular atrophy (SMA), fragile X syndrome, and myotonic dystrophy. Understanding these molecular mechanisms will serve as the basis for future development of effective therapies.