The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a key signaling node, universal to eukaryotic cells, which links the sensing of nutrients to the coordinated regulation of nutrient metabolism. mTORC1 has the ability to integrate signals from a variety of sources, including intracellular nutrients and secreted growth factors. The activation state of mTORC1 is tightly controlled through a small G protein switch involving the TSC1-TSC2-TBC1D7 complex (the TSC complex) and the Ras-related small G protein Rheb. The direct phosphorylation and inhibition of the TSC complex by the protein kinase Akt provides the major mechanistic link between growth factor signaling and mTORC1. Current evidence indicates that this signal is integrated with amino acid sensing pathways upstream of mTORC1 through independent spatial control over the subcellular localization of the TSC complex and mTORC1 to the surface of the lysosome. Our data suggest that both physiological growth signals and common oncogenic events in cancer activate mTORC1 through mechanisms leading to dissociation of the TSC protein complex from the lysosomal subpopulation of Rheb, which is required for mTORC1 activation.

The physiological and pathological activation of Akt and mTOR signaling results in a shift from catabolic processes to anabolic biosynthetic processes. Through unbiased genomic and metabolomic approaches, we have found that, in addition to its established roles in promoting protein synthesis and inhibiting autophagy, mTORC1 stimulates changes in specific metabolic pathways through transcriptional and posttranslational effects on metabolic enzymes. In this manner, mTORC1 serves to link growth signals to metabolic processes that promote the growth of cells, tissues, and tumors, including the de novo synthesis of proteins, lipids, and nucleotides. I will discuss our latest data on additional metabolic enzymes under direct control of the PI3K-mTOR network that contribute to an integrated metabolic program underlying cell growth in both normal and cancer cells.

The protein/DNA complex known as the kinetochore links chromosomes to the microtubules of the mitotic spindle. The kinetochores of budding yeast cells appear to be elementary, unimodular versions of the multimodule kinetochores of metazoan cells. Most of the 50–80 distinct protein species that make up a yeast kinetochore are organized into well-defined subcomplexes. Prof. Harrison has been studying the structures of these subcomplexes using a diverse set of approaches including cryoEM and X-ray crystallography. In this seminar, he will present the latest advances of his group on the structure, function, and evolution of the kinetochore.

The amyloid cascade hypothesis for Alzheimer disease ((Hardy and Selkoe, 2002; Hardy and Higgins, 1992; Selkoe, 1991), updated in (Karran et al., 2011) provides a linear model for the pathogenesis of AD with Aβ accumulation upstream and Tau pathology, inflammation, synaptic dysfunction, neuronal loss and dementia downstream, all interlinked, initiated and driven by Aβ42 peptides or oligomers. The genetic mutations causing familial Alzheimer disease seem to support this model. The nagging problem remains however that the postulated causal, and especially the ’driving’ role of abnormal Aβ aggregation or Aβ oligomer formation could not be convincingly demonstrated until now. Indeed, many questions (e.g. what causes Aβ toxicity, what is the relation between Aβ and Tau pathology, what causes neuronal death, why is amyloid deposition not correlated with dementia etc…) were already raised when the amyloid hypothesis was conceived 25 years ago. These questions remain in essence unanswered. It seems that the old paradigm is not tenable: the amyloid cascade is too linear, too neurocentric, and does not take into account the long time lag between the biochemical phase i.e. the appearance of amyloid plaques and neuronal tangles and the ultimate clinical phase, i.e. the manifestation of dementia. The pathways linking these two phases must be complex and tortuous. We have called this the cellular phase of AD (De Strooper and Karran, 2016) to suggest that a long period of action and reaction involving neurons, neuronal circuitry but also microglia, astroglia, oligodendrocytes, and the vasculature underlies the disease. In fact it is this long disease process that should be studied in the coming years. While microglia are part of this process, they should not be considered as the only component of the cellular phase. We expect that further clinical investigations and novel tools will allow to diagnose the effects of the cellular changes in the brain and provide clinical signs for this so called preclinical or prodromal AD. Furthermore the better understanding of this phase will lead to completely novel drug targets and treatments and will lead to an era where patients will receive an appropriate therapy according to their clinical stage. In this view anti-amyloid therapy is probably only effective and useful in the very early stage of the disease and AD does no longer equal to dementia. We will discuss in our talk how single cell technology and transplantation of human iPS cells into mouse brain allow to start to map in a systematic way the cellular phase of Alzheimer’s Disease.

External speaker: Frank Uhimann, Francis Crick Institute, London