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Pathological forms of tau and cytoskeleton alterations: deciphering the molecular basis of tauopathies

Summary of the project

Background

Tau, a microtubule (MT)-associated protein, is abundant in neurons. It was initially identified as a MT stabiliser and bundler, but was subsequently shown to also be involved in actin organisation. Tau contributes to axonal transport and synaptic function as well as cell signalling and DNA repair. Tau dysfunction and aggregation are the main hallmarks of Alzheimer’s disease (AD) and related tauopathies, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) that are caused by mutations in tau. Animal models expressing FTDP-17 tau mutants have defective cytoskeleton-dependent cellular processes, such as synapse plasticity and axonal transport.
How exactly FTDP-17 tau mutants alter cytoskeletal organisation remains to be elucidated.

Objectives

The aim of the PhD project is to determine the impact of FTDP-17 mutated forms of tau on the microtubule and actin cytoskeletons of neurons.

Methods and expected results

Primary cultures of mouse hippocampal neurons will be transduced with lentiviral vectors expressing fluorescent wild-type or mutated tau. Specific fluorescent markers (fluorescent-tagged actin and MT end-binding proteins, EBs) will be used to determine how tau mutants affect actin turnover in spines and MT dynamics along axons/dendrites. Actin turnover will be measured by FRAP methods, and MT dynamics by time-lapse confocal microscopy. Any alterations to actin or MT dynamics will be analysed in the context of neuronal morphology, i.e. axon/dendrite length and branching, or spine shape and density. Using expansion protocols and super-resolution microscopy approaches, we will determine the effects of tau mutants on MT arrays (length, density, bundling) and on actin nanostructures (periodicity of actin-based axonal rings, actin trails) present in neuronal processes. These techniques will also allow us to investigate whether wild-type and mutated tau specifically target certain types of MT populations (dynamic tyrosinated or stable detyrosinated/acetylated MTs, single or bundled MTs) or actin structures (trails, hotspots or rings). These data will be complemented by experiments in cell-free systems to determine the biochemical parameters controlling the tau-cytoskeleton interaction.
Altogether, results should give a better understanding of the molecular pathways leading to cytoskeleton alterations in tauopathies.

Required skills

We are seeking a highly motivated student with background in cell biology. Additional knowledge in microsocpy would be appreciated.

Contact

Candidates should send their CV, as well as the name and contact details of two academic references, to isabelle.arnal@univ-grenoble-alpes.fr and anne.fourest-lieuvin@univ-grenoble-alpes.fr

Téléchargement(s)

GIN-EqArnal_sujet-these-2021_IArnal-AFourestLieuvin_20210305.pdf (PDF, 47 Ko)

Mise à jour le 5 mars 2021

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