NEUROTROPHINS-ARMS

Molecular mechanisms underlying BDNF functions in the brain: role of ARMS protein

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 Obiettivo del progetto (Objective)

'Neurotrophins are growth factors including NGF, BDNF, NT-3 and NT-4, which function in cell survival, differentiation, apoptosis, axonal and dendritic growth, and plasticity in the nervous system. Additionally, BDNF has been implicated in human brain pathologies, such as depression, Alzheimer, Huntington, Parkinson, etc. Neurotrophins bind to two different sets of receptors, Trk and p75 receptors, to mediate their functions. Trk activation leads to its phosphorylation in tyrosine and the phosphorylated residues work as docking sites for different adaptor molecules, such as Shc, PLC-γ, FRS-2, SH2B and APS. Recently, a new molecule, ARMS/Kidins220, has been described in association with Trk receptors. ARMS is tyrosine phosphorylated in primary hippocampal and cortical neurons in response to neurotrophins, and is involved in the sustained MAPK mediated by neurotrophins. My work hypothesis is that ARMS/Kidins220 may be an important molecule in neurotrophin functions. For this reason, we propose the study of ARMS/Kidins220 in the differentiation, dendritic branching and neuronal synaptic plasticity mediated by BDNF. The study will be carried out using biochemical and cellular techniques together with molecular biology and genetic approaches. The detailed study of ARMS/Kidins220 will provide a better understanding of the neurotrophin functions as well as the molecular mechanisms that regulate neurotrophin actions and its potential role in nervous system pathologies.'

Introduzione (Teaser)

Neurotrophins are a family of proteins falling under the class of growth factors. They send signals to specific cells to grow, differentiate or survive.

Descrizione progetto (Article)

In particular, neurotrophins promote the survival of neurons by preventing the latter from starting on the path to programmed cell death (apoptosis). Their functions are mediated on the strength of being able to bind with receptors Trk and p75. One of these neurotrophins is the brain-derived nerve factor (BDNF) that also functions in cell axonal and dendritic growth, as well as plasticity in the nervous system.

Trk activation leads to its phosphorylation (addition of a phosphate group to a protein), following which residues act as docking sites for various adaptor molecules. One of these is the recently discovered ARMS/Kidins220. This has been linked to neurotrophin signalling through primary hippocampal and cortical neurons. Researchers have cause to believe that BDNF and ARMS may function together, as changes in BDNF function/expression have been implicated in human brain pathologies. These include depression, and Alzheimer's and Parkinson's diseases.

The 'Molecular mechanisms underlying BDNF functions in the brain: role of ARMS protein' (Neurotrophins-ARMS) is working on the hypothesis that ARMS/Kidins220 may be an important molecule in neurotrophin functions. Team members are using biochemical and cellular techniques in combination with molecular biology and genetic approaches to study ARMS/Kidins220.

Investigations aim to discover if the expression pattern of ARMS is similar to that of neurotrophins and neurotrophin receptors when the nervous system is still in its development phase. Also of interest is whether ARMS expression levels undergo any changes in cases of brain pathologies where BDNF is altered. Project partners are also studying the role played by ARMS in BDNF-induced dendritic growth and spine/synapse formation during nervous system development. Another project objective is to examine what, if any, role ARMS plays in BDNF-mediated synaptic plasticity during adulthood.

In work done to date, studies have revealed that ARMS expression is very high during the embryonic (developmental) stage of the nervous system, declining shortly after birth. BDNF has been shown to participate in massive dendritic growth and synapse formation during nervous system development. The Neurotrophins-ARMS project has experimented with reducing ARMS levels to examine dendritic branching and spine dynamics in neurons. Data indicate that ARMS is important for the correct development of form and structure in dendritic arbours and spines during activity and BDNF-dependent developmental periods.

As project work continues, researchers are studying the role of ARMS in BDNF-mediated synaptic plasticity during adulthood. Results obtained so far suggest that ARMS is an important downstream substrate that appears to mediate BDNF functions already investigated.

Better knowledge of ARMS/Kidins220 promises to enhance our understanding of neurotrophin functions and the molecular mechanisms playing a role in neurotrophin actions. This is very important as the medical world seeks to better understand the potential role of such growth factors in nervous system pathologies.