Tau structural biology: PhD student in Lille, France
The Integrative Structural Biology team headed by Isabelle Landrieu is dedicated to Investigation of the structural basis and molecular mechanisms underlying Tau biological functions, and the impact of their deregulation in tauopathies (http://groupe-rmn-modelisation.univ-lille1.fr/).
Tau exhibit specific characteristics such as numerous post-translational modifications and regions rich in proline residues, modulating its interactions, as well as its propensity to aggregate in proteinopathies.
At the heart of our work are biophysical multidisciplinary methods for characterizing the structure of proteins, as well as the interactions between them, such as Nuclear Magnetic Resonance spectroscopy, X-ray cristallography and cryo-electron microscopy.
Projects are pursued in close collaboration with experts in the AD field in Lille within the LabEx DISTALZ (National consortium against AD, http://distalz.univ-lille2.fr/), including the team “Alzheimer and tauopathies” headed by Luc’s Buée (http://www.lucbuee.fr/). We are proud to offer this unique workplace culture that inspires interdisciplinary collaboration. Within this environment we are open to expression of various perspectives and ideas.
In 2021, we expect to welcome PhD students, post-doctoral fellows and engineers on several projects that are now funded. This is a great opportunity to join the team and Distalz as an early stage researcher, and bring your scientific talent and enthusiasm to contribute to our projects. The PhD candidates will obtain their PhD degree from Lille University.
We are looking for highly motivated, experimentally skilled young scientists, with background in one or several of the following fields : Protein Biochemistry, Structural Biology, Cell Biology, Microscopy Imaging
The daily activities of the early-stage researcher consist mainly in research, but it is also expected that the candidate participates in the internal seminars, courses and local and international scientific events. Collaboration with other PhD candidates, postdoctoral researchers and other members of the team and consortium will be encouraged.
You can reach us with a CV and motivation letter at firstname.lastname@example.org
Tau seeds in human-derived extracellular vesicles: which proteoforms?
UMR- S 1172, ‘Alzheimer&Tauopathies’ Lille Neuroscience & Cognition research centre. Contact: Morvane COLIN <email@example.com>
This project, under the supervision of Dr Morvane Colin, will take place in Lille in the ‘Alzheimer&tauopathies’ Inserm team (Lille Neuroscience & Cognition – UMRS1172). Our team is an internationally recognized laboratory on tau proteins, which is part of the LabEx DISTALZ (National consortium on AD) and LiCEND (Lille Centre of Excellence for Neurodegenerative Disorders). We are interested in tau proteins and their aggregation in neurofibrillary tangles, a lesion correlated to cognitive impairment in Alzheimer’s disease. In some tauopathies including AD, PSP and Pick, it appears that the abnormal accumulation of tau proteins, in which the misfolding and aggregation process is a common feature, progress in a nucleation-dependent manner (1,2). In this context, the group of Morvane Colin has a wide expertise in the prion-like tau propagation and developed new dedicated murine models and in vitro cell based assays (3-8). Those models are now proposed for immunotherapy strategies (collaboration UCB Biopharma, Belgium) (9). Knowing that tau lesion might progress in a prion-like mechanism of transmission, the remaining questions are now around molecular species responsible for propagation/seeding and their targeting by targeted strategies. We know and have demonstrated in our in vitro and in vivo models that secreted tau is found in extracellular vesicles (6) suggesting that these structures play an important role in disease progression.
We now would like to transfer our knowledge to human samples and to decipher 1) the place of human extracellular vesicles in tau spreading and 2) the molecular species present in these vesicles which are responsible for tau seeding. To reach these objectives, extracellular vesicles will be isolated from human biological fluids (CSF, plasma…) from non-demented subjects and individuals presenting tauopathies (AD, PSP, PiD) thanks to our close collaboration with the memory clinic (MMRC, ‘Lille Resources and Research Memory Centre’, Prs F. Pasquier and V. Deramecourt). We will use complementary innovative approaches to 1) evaluate the seeding properties of tau species circulating in extracellular vesicles and 2) to generate state-of-the art mass spectrometry tau profile from these shuttles (Collaboration S. Lehmann, D. Bougard Montpellier), especially the seeding species present in PMCA amplicon.
M. Colin’s bibliographic references relative to this project: (1) Colin M et al., (2020) From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy. Acta Neuropathol. 2020 Jan;139(1):3-25. (2) Mudher A et al., (2017) What is the evidence that tau pathology spreads through prion-like propagation? Acta Neuropathol Commun. 2017 Dec 19;5(1):99. (3) Richetin K. et al., (2020) Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer’s disease. Nat Neurosci 2020 Nov 9. doi: 10.1038/s41593-020-00728-x. (4) Dujardin S et al., (2018) Different tau species lead to heterogeneous tau pathology propagation and misfolding. Acta Neuropathol Commun. 2018 Nov 29;6(1):132. (5) Tardivel M et al., (2016) Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies. Acta Neuropathol Commun. 2016 Nov 4;4(1):117. (6) Dujardin S et al., (2014) Ectosomes: a new mechanism for non-exosomal secretion of tau protein. PLoS One. 2014 Jun 27;9(6):e100760. (7) Dujardin S et al., (2014) Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies. Acta Neuropathol Commun. 2014 Jan 30; 2:14. (8) Caillierez R et al., (2013) Lentiviral delivery of the human wild-type tau protein mediates a slow and progressive neurodegenerative tau pathology in the rat brain. Mol Ther. 2013 Jul;21(7):1358-68. (9) Albert M et al., (2019) Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody. Brain. 2019 Jun 1;142(6):1736-1750.