My research group aims to understand how the cytoskeleton is regulated through signalling processes, and how this contributes to the formation of neuronal networks during development and their maintenance during ageing. For this, we make use of the fruit fly Drosophila where processes of neural development and ageing occur much faster, can be investigate with highly efficient experimental and genetic strategies, and lead to understanding that usually applies to higher organisms including humans. For example, signalling pathways known to be affected in ageing can be easily manipulated in our model, and their effects analysed in as little as 5 weeks, as compared to 15 months in mice. Notably, signs of ageing in fly neurons resemble the typical hallmarks of neuronal ageing in primates. See my website for more details.
THE MICROTUBULE CYTOSKELETON
MTs are filamentous polymers which are continuously extending and shortening. This dynamics is regulated through MT-binding proteins (MTBPs). Accordingly, MTBPs are the essential factors maintaining microtubule networks and they are subject to tight regulation by a variety of signalling pathways. MTs are indispensable for all cell types where they play multiple functions in maintaining cell shape, promoting growth and migration, communicating the external with the intracellular environment and organising the cellular content including signalling events.
Neurons are particularly dependent on MTs. This is because neurons have extreme morphologies, in particular their delicate cable-like axons which can expand over distances of up to a meter in humans. The structural backbones of axons is a bundle of parallel MTs running all along their core. Axonal MTs drive axon growth, they determine the morphology and structural resistance of axons and are used as highways for life-sustaining transport. MT decay often lies at the root of neuronal degeneration caused by ageing, disease or injury.
FORMING AND MAINTAINING NEURONAL NETWORKS
Neurons are specialised to form neuronal networks; they connect to other neurons and cells establishing synaptic connections to pass on electrical messages. Aberrations of the networks caused by developmental or neurodegenerative disease, ageing or by injury have debilitating effects on behaviour or even survival.
In order to connect body or brain regions over distances up to a meter away in humans, neurons extend long and thin axons. Understanding how the growth of axons towards specific targets is regulated and how they are maintained for an organism’s lifetime, poses a biological challenge. We contribute to this challenge by studying MTs, the signalling pathways that orchestrate axonal MTs and their direct regulators in the context of growth and maintenance.
THE CYTOSKELETON, AGEING AND NEURONAL PATHOLOGIES
During physiological ageing, there is a progressive occurrence of axonal atrophy and synaptic decay and it is estimated that by the age of 80 we have lost about 40% of axonal fibres. This decrease in neuronal mass is greatly exacerbated in neurodegenerative diseases. It is suspected that the decay of axons and their synapses is one important reason for decreasing cognitive capability and mobility as is typically observed during ageing and neurodegenerative pathologies. Yet, what causes axonal and synaptic atrophy remains largely unknown.
We hypothesise that the loss of axons and their synapses occurring during ageing or in neurodegenerative diseases can be caused by defective microtubule regulation. Accordingly, neuronal microtubules are altered during ageing and a number of MTBPs involved in microtubule bundle maintenance (e.g. MAP1B, Tau, kinesins and dystonin) are associated with neurodegenerative disease. Several of our projects aim to understand how ageing or pathological mutations affect signalling pathways and how these, in turn, affect MT regulation and eventually neuronal networks. Our work provides new opportunities to understand decay processes occurring in the nervous system during ageing and/or neurodegeneration.
Ongoing projects
- The study of neuronal microtubule networks and their regulation during the formation and maintenance of axons and their synapses
- Linking signalling pathways to microtubule regulation
- Investigating Tau-dependent mechanisms of neurodegeneration
- Understanding the cell biology of neuronal ageing
Sanchez-Soriano Group (Neuronal Cytoskeleton Laboratory) 