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Neuronal plasticity: cell-based strategy for target identification and validation

Ana Mingorance-Le Meur¹ and Timothy P. O’Connor²

Correspondence: (Login to view email address)

1. University of British Columbia (Vancouver, Canada)
2. University of British Columbia (Vancouver, CA)

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Document Type:

Poster

Date:

Received 13 January 2009 02:16 UTC; Posted 13 January 2009

Subjects:

Molecular Cell Biology, Neuroscience, Pharmacology

Tags:

• cell based
• target identification
• target validation
• neuronal networks
• growth cone
• cell migration
• calpain
• brain
• branching
• Cell
• plasticity
• regeneration
• neuron
• Candidate
• neurite
• sprouting
• therapeutic

Abstract:

While growing neurites are relatively plastic during development, their plasticity levels drop rapidly as neurons mature and become integrated into neuronal networks. As a consequence, the central nervous system ability to reorganize itself in response to injury or disease is insufficient. One of the main limitations for the design of therapeutic strategies to enhance neurite sprouting following neurological diseases is our poor understanding of the mechanisms underlying neurite structural plasticity.

To overcome this limitation, we have implemented a strategy to identify, characterize and validate the most therapeutically relevant drug targets to modulate neuronal plasticity. This strategy is based on the hypothesis that the molecular regulation of the neurite shaft (controlling its ability to sprout) shares similarities with other cell systems. In an initial selection step (1), candidate targets are identified from the literature based on predetermined criteria (e.g. involvement in cell migration and growth cone collapse). (2) Compounds acting on those targets are tested in a neuronal cell-based assay for their effects on neurite sprouting as well as for early detection of undesired effects. (3) The selected targets are further analyzed during a verification step where their subcellular expression and activity is assessed. The regulation of the activity of the potential targets by branching factors is also determined at this point. (4) Once the biological relevance has been established, the signalling pathway in which the potential targets operates within neurons is mapped using activity reporters to uncover additional potential targets.

This candidate approach, combined with the use of primary neurons, is designed to increase the probability of identifying suitable targets at the same time that it minimizes costs and time to validation. By using this strategy, we have been able to identify a set of proteins controlling neuronal sprouting together with an unsuspected mechanism of regulation of structural plasticity in neurons.

Presented at:

MipTec 2008, Basel, Switzerland, 16 October 2008

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Mingorance-Le Meur, Ana and O’Connor, Timothy. Neuronal plasticity: cell-based strategy for target identification and validation. Available from Nature Precedings <http://dx.doi.org/10.1038/npre.2009.2780.1> (2009)

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