Louis-Jeantet 2014 Prize Lecture

Monday 1 September

11:30-12:30, Grand Auditorium

Introduction by Jürg Schifferli, CH

Watch an interview with Elena Conti.			Elena Conti Max Planck Institute of Biochemistry, Martinsried, DE Mechanisms of RNA degradation: the exosome complex RNA degradation serves a multitude of functions in all domains of life. RNA decay modulates the abundance of transcripts and is the ultimate step in quality control pathways that detect and eliminate defective RNAs. A conserved multi-protein complex, the exosome, is the main nuclease that degrades eukaryotic RNAs from their 3' end. Related complexes are also present in bacteria and archaea, highlighting the importance of this ancient molecular machine. The eukaryotic exosome contains a core of 10 different proteins with a molecular mass of 400 kDa (Exo-10). Using biochemical and structural studies, we have shown that nine subunits are catalytically inert but form a hollow chamber that threads unfolded RNA substrates to the only catalytically active subunit of the core complex. The catalytic core of the exosome is present in both the nuclear and the cytoplasmic compartments. Auxiliary factors have been identified that bind and regulate the exosome in a compartment-specific manner. In the nucleus, the exosome associates with a set of proteins that include a ribonuclease and an RNA helicase. In the cytoplasm, the exosome associates with the Ski complex, a 400 kDa protein assembly that is also centered on an RNA helicase. Current structural and biochemical data suggest that the regulatory complexes gate the entrance to the exosome core. The emerging picture is that there are conceptual similarities in how the exosome and proteasome complexes prepare and channel their RNA and protein substrates for controlled degradation. Biography Elena Conti studied Chemistry at the University of Pavia in Italy and received her Ph.D. in 1996 from the Faculty of Physical Sciences at Imperial College in London. For her post-doctoral studies, she joined the laboratory of John Kuriyan at the Rockefeller University in New York, where she worked on the mechanisms of nuclear import. In 1999, Elena Conti established her own research group at the European Molecular Biology Laboratory in Heidelberg. Here, she started to study RNA export and its connections to RNA maturation, surveillance and turnover. In particular, her group has been working on the molecular mechanisms of nonsense-mediated mRNA decay, an mRNA surveillance pathway that detects and degrades defective mRNAs with premature stop codons, and on the actual mechanisms of RNA degradation by the exosome complex. To obtain molecular insights into these processes, her group uses a combination of structural biology, biochemistry and biophysical approaches. Since 2007, Conti is a director at the Max Planck Institute of Biochemistry in Munich, where she is head of the Department of Structural Cell Biology.

Watch an interview with Denis Le Bihan.			Denis Le Bihan NeuroSpin, CEA Saclay Center, Gif-sur-Yvette, FR Diffusion MRI: What the water molecule tells us about the brain Among the astonishing Einstein’s papers from 1905 there is one which unexpectedly gave birth to a powerful method to explore the brain. Molecular diffusion was explained by Einstein on the basis of the random translational motion of molecules which results from their thermal energy (Einstein, 1905). In the mid 1980s I showed that water diffusion in the brain could be imaged using MRI. During their random displacements water molecules probe tissue structure at a microscopic scale, interacting with cell membranes, thus providing unique information on the functional architecture of tissues. Water diffusion MRI has been extraordinarily successful. Its main clinical domain of application has been neurological disorders, especially for the management of patients with acute brain ischemia. With its unmatched sensitivity water diffusion MRI provides patients with the opportunity to receive suitable thrombolytic treatment at a stage when brain tissue might still be salvageable, thus avoiding them terrible handicaps. On the other hand, it was found that water diffusion is anisotropic in brain white matter, because axon membranes limit molecular movement perpendicularly to the axonal fibers. This feature can be exploited to produce stunning maps of the organization in space of the white matter tracks and brain connections in just a few minutes, as well as to provide information on white matter microstructure and integrity. With diffusion tensor MRI (a variant of diffusion MRI to study more specially diffusion anisotropy) it has been shown that some psychiatric disorders, such as schizophrenia, might result from faulty brain connections. More recently, diffusion MRI has been also used in the body for the detection and treatment monitoring of cancer lesions and metastases, as water diffusion slows down in malignant tissues in relation to the cell proliferation. With diffusion MRI no radioactivity is involved, and images can be obtained with high resolution and excellent sensitivity and specificity. The versatile concept and the potential of diffusion MRI, both for research and clinical applications, will be briefly reviewed, along with some historical developments which led to those concepts during the last 30 years. Biography Dr. Denis Le Bihan is a physician (radiologist) and physicist who has made outstanding contributions to the development of new imaging methods allowing, in particular to study human brain function. Especially, he pioneered the use of Diffusion Magnetic Resonance Imaging for brain imaging studies and has spared no effort during the last 30 years to continuously improve the potential of this method. Diffusion MRI has been used worldwide for the investigation of brain anatomy, connectivity and function, as well as for the management of patients with neurological disorders, such as stroke, white matter diseases or mind disorders. D. Le Bihan is the Director and Founder of NeuroSpin, a prominent institution of the French Atomic Energy Commission aimed at developing methods and technologies to understand the brain through magnetic resonance imaging (MRI) at ultra-high magnetic field. D. Le Bihan is a Member of the Institut de France, Academy of Sciences, as well as the French Academy of Techonologies. He has already received important international awards for his scientific and medical achievements.