SYNAPSE STABILITY

"Molecular Analysis of Synapse Formation, Maintenance and Disassembly at the Drosophila neuromuscular junction"

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 Obiettivo del progetto (Objective)

'The refinement of neuronal circuits requires both a stabilization of existing synaptic connections and a disassembly of previously functional synapses. While the mechanisms of synapse formation have been extensively studied, very little is known about the molecular mechanisms that are responsible for the stabilization of synaptic connections. Any inappropriate loss of synaptic stability will lead to disruptions of neuronal circuits and finally to neurodegenerative disease. Therefore, the identification of the molecular mechanisms that regulate synapse stability versus disassembly may help to understand how synaptic circuits are modified in response to signaling events and may provide useful insights towards our understanding of neurodegenerative disease. I am combining the advantages of Drosophila genetics, cell biology and physiology with a high-resolution assay for synapse retraction to identify and characterize genes involved in synapse formation, stability and disassembly. My postdoctoral work has highlighted the importance of a presynaptic cytoskeletal network that links cell adhesion molecules to the underlying actin and microtubule cytoskeleton to achieve normal synapse formation and stability. Here I propose to define the signaling systems that control the assembly and stability of the presynaptic network during synapse formation and maintenance. In the first aim I will focus on the adaptor molecule Ankyrin2 that has the potential to directly link synaptic cell adhesion molecules to the presynaptic microtubule cytoskeleton. The second aim addresses how actin dynamics contribute to normal synapse formation and stability. Finally, I will use forward genetic approaches to identify novel molecules required for synaptic stability. Together these projects will provide insights into the molecular mechanisms that regulate synapse stability in response to intrinsic and extrinsic signaling systems within neuronal circuits.'

Introduzione (Teaser)

Slowly but surely, the specific molecules, cells and genes that are responsible for a host of neurodegenerative diseases are being identified.

Descrizione progetto (Article)

Neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's disease are characterised by the progressive loss of function or structure of neurons (nerve cells). While the symptoms of these diseases are quite different, research has found that they resemble each other on a sub-cellular level. Understanding the communication between brain neurons, moderated by the synapses, and their behaviour or interconnections is crucial to determining the underlying causes of these diseases.

The quickest way to learn about synapses is by manipulating them and observing them in drosophila, the common fruit fly. Drosophila can be bred quickly, particularly with the desired mutations that help researchers pinpoint brain cell behaviour and the specific genes involved in neurodegenerative diseases.

The understanding of neuronal circuits requires both stabilisation of existing synaptic connections and a disassembly of previously functional synapses, which can be readily accomplished using drosophila. While the mechanisms of synapse formation have been studied extensively, very little is known about the molecular mechanisms responsible for stabilising synaptic connections. Any inappropriate loss of synaptic stability will lead to disruptions of neuronal circuits and finally to neurodegenerative disease.

This research is being led by a fully funded EU project called 'Molecular analysis of synapse formation, maintenance and disassembly at the drosophila neuromuscular junction'. The project is revealing how synaptic circuits are modified in response to signalling events, by identifying the molecular mechanisms that regulate synapses.

More specifically, the project is combining drosophila genetics, cell biology and physiology with detailed testing on synapse behaviour to identify and characterise genes involved in synapse formation, stability and disassembly. The research team has already revealed the specific mechanisms needed to achieve normal synapse formation and stability.

The researchers have also identified key genes and specific molecules (known as novel cell adhesion molecules or CAMs) that are implicated in the formation and stability of synapses. The findings are valuable for ongoing studies, bringing us a step closer to understanding neurodegenerative diseases. Continued analysis of potential regulation of this molecular network during synapse formation and maintenance should greatly advance our current understanding of the particular processes involved. The next logical step would be to postulate a cure based on this information.