Invited speakers
Laura Aradilla Zapata (Molecular Biophysics of the Cell, Univ. Saarland, Germany)
Vimentin Intermediate Filaments Stabilize Dynamic Microtubules by Direct Interactions
Abstract
Growing evidence suggests that the manifold tasks of the cytoskeleton rely on the interactions between its filamentous components—actin filaments, intermediate filaments, and microtubules.
However, the nature of these interactions and their impact on cytoskeletal dynamics are largely unknown. Here, we show in a reconstituted in vitro system that vimentin intermediate filaments stabilize microtubules against depolymerization and support microtubule rescue. To understand these stabilizing effects, we directly measure the interaction forces between individual microtubules and vimentin filaments. Combined with numerical simulations, our observations provide detailed insight into the physical nature of the interactions and how they affect microtubule dynamics. Thus, we describe an additional, direct mechanism by which cells establish the fundamental cross talk of cytoskeletal components alongside linker proteins.
Isabelle Arnal (GIN - Grenoble Institut Neurosciences)
Microtubule regulation from the lumen
Abstract
Microtubules are hollow tubes that can grow and shrink alternately. In neurons, dynamic microtubules coexist alongside long-lived stable microtubules that are essential for neuronal architecture and function. Proteins located in the lumen of microtubules, known as MIPs (Microtubule Inner Proteins) are thought to contribute to microtubules stability, by analogy with the extreme microtubule stability in cilia/flagella required to resist high beating frequency and controlled by MIPs. MIPs have long been observed in most neuronal microtubules, but their identity was unknown until we identified the first as MAP6. I will present our recent work about the molecular mechanisms underlying neuronal microtubule stabilisation and organisation by two members of MAP6 family, MAP6 and MAP6D1.
Roland Brandt (Dpt of Neurobiology, Univ. Osnabrück, Germany)
Why kiss-and-hop explains that tau does not stabilize microtubules and does not interfere with axonal transport (at physiological conditions)
Abstract
Tau is a microtubule-associated protein that is enriched in the axonal process of neurons. Post-translational modifications of tau have been implicated in the development of tauopathies characterized by defects in axonal transport, neuronal atrophy, and microtubule disassembly.
Although tau is almost quantitatively bound to microtubules under physiological conditions, it does not significantly affect axonal transport. Furthermore, acute or chronic tau deficiency does not result in significant destabilization of neuronal microtubules, challenging the classical view that disease-related tau modifications directly cause axonal microtubule collapse. We discuss how the rapid interaction kinetics of the tau-microtubule interaction, which we previously termed the kiss-and-hop interaction, explains why tau does not affect microtubule-dependent axonal transport but still allows tau to modulate microtubule polymerization. In contrast, tau modifications that slow down the kinetics of the tau-microtubule interaction and increase the residence time of tau at a microtubule interaction site can disrupt axonal transport and cause dendritic atrophy. We discuss the consequences of such a gain-of-toxicity mechanism in terms of the development of disease-modulating drugs that target the tau protein.
Karin John (LIPhy - Laboratoire Interdisciplinaire de Physique, Grenoble)
Lattice dynamics in microtubules: active and passive mechanisms
Abstract
Microtubules are key structural elements of living cells that are crucial for cell division, intracellular transport and motility. They are dynamic polymers, which grow and shrink by addition and removal of tubulin dimers at their extremities. Within the microtubule shaft, dimers adopt a densely packed and highly ordered crystal-like lattice structure, which is generally not considered to be dynamic.
Recent experiments have shown that microtubules exhibit a lattice dynamics far away from the extremities. This dynamics manifests itself as localized incorporation of free tubulin into the microtubule shaft, either spontaneously or facilitated by microtubule associated proteins, e.g. molecular motors and severing enzymes. A major biological corollary of such fresh tubulin incorporation events is the increased stability of dynamic microtubules.
The origin and underlying mechanisms of tubulin incorporation are still an open question. Here I theoretically explore potential mechanisms of lattice turnover. Thereby I concentrate on two cases: the spontaneous lattice turnover at structural defects [1] and the lattice dynamics stimulated by molecular motors, where lattice vacancies may play a major role [2,3].
[1] Schaedel et al. Nat. Phys. 15, 830 (2019)
[2] Triclin et al. Nat. Mater. 20, 883 (2021)
[3] Lecompte & John PRX LIFE 1, 013012 (2023)
Devrim Kilinc (Institut Pasteur de Lille)
Axonal and dendritic transport in the context of Alzheimer’s disease
Abstract
Transport of cargo via motor proteins operating on microtubules is crucial for the proper functioning of the nervous system. Key proteins linked to Alzheimer’s disease pathogenesis are linked to microtubule-based transport either as cargo (e.g., amyloid precursor protein) or as regulators of microtubule structure (e.g., tau). Synaptic dysfunction is one of the earliest events in Alzheimer’s disease and the correct sorting of presynaptic and postsynaptic cargo to axons and dendrites (and eventually into dendritic spines) rely on microtubule motors. In recent years, studying axonal and dendritic transport has been facilitated by the use of multi-chamber microfluidic devices. In this talk, I will illustrate axonal transport experiments related to Alzheimer’s disease, based on different model systems (from primary rodent neurons to human induced neurons).
Andreas Prokop (Division of Molecular & Cellular Function, Univ. Manchester, UK) - visio
The microtubule cytoskeleton – throwing a lifelong lifeline to neuronal axons
Abstract
Axons are the long and slender processes of nerve cells that form the biological cables wiring nervous systems. In humans, they can be up to 2m long at diameters of less than 15µm. These delicate structures must survive for a century, despite being exposed to continued mechanical challenges. Naturally, they are key lesion sites in ageing and neurodegeneration.
Axons can survive long-term through the homeostasis of a complex interdependent network of cell biological processes occurring locally in axons far away from their cell bodies. Virtually all these processes depend on loose parallel bundles of microtubules that run uninterrupted all along axons. These bundles provide the highways for motor protein-driven cargo transport essential to supply cell biological processes and position them appropriately in the axon.
Furthermore, these microtubules are pivotal building blocks for any growth or branching events occurring in axons. Therefore, knowing the origins, dynamics and maintenance of these microtubule bundles is key for our understanding of axons.
In this presentation, I will explain how axonal microtubule bundles are formed, how they are organised, the challenges they face, some key concepts of their regulation through microtubule-binding proteins that can maintain these bundles long-term, and the ‘dependency cycle of local axon homeostasis’ as a microtubule-based models that provides new perspectives for research into neurodegeneration.
Short talks:
Marie-Charlotte Emperauger_(LUMIN, ENS Paris-Saclay)
Holographic two-photon microscope for real-time 3D single-particle tracking
Marie Sellier-Prono (LPENS) and Cécile Appert-Rolland (IJCLab, Paris-Saclay)
Models for axonal transport
Carsten Janke (Institut Curie, Orsay)
The impact of the tubulin code on microtubule functions
