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The University of Southampton
Biological Sciences

Axonal Transport in Motor Neurons: from in vitro screens to real time in vivo assays Seminar

Time:
14:00
Date:
24 February 2012
Venue:
Building 37 Level4, Senate Room

For more information regarding this seminar, please telephone Beatrice Murphy on 023 8059 5374 or email b.j.murphy@southampton.ac.uk .

Event details

Axonal transport is crucial for the maintenance of neuronal function and survival. As a result, deficits in transport are known to result in neuronal degeneration in several areas of the nervous systems.

Axonal transport is crucial for the maintenance of neuronal function and survival. As a result, deficits in transport are known to result in neuronal degeneration in several areas of the nervous systems (1). However, the functional link between axonal transport deficits and disease progression remains unclear. To identify novel players in the regulation of the axonal retrograde transport pathway, we have established robust methods to carry out siRNA screen in ES-derived motor neurons. As a proof of principle, we have used a library of siRNAs directed against genes involved in endocytosis and membrane traffic. Positive and negative regulators of axonal retrograde transport were identified and candidates were validated using secondary screens. Hence, siRNA approaches represent a powerful tool to investigate traffic events in neurons and for the discovery of novel players in this biological process. To extend our understanding of the regulation of axonal transport during disease progression, we have established in parallel an in vivo assay that allows us to monitor retrograde transport in the intact sciatic nerve in anaesthetised mice (2). This assay permits the quantitative analysis of axonal transport in animal models of neurodegeneration (e.g. amyotrophic lateral sclerosis - ALS; spinal and bulbar muscular atrophy - SBMA) at different stages of disease. This analysis revealed significant alterations in axonal retrograde transport from a presymptomatic stage in an established model of ALS, suggesting a causal role for these alterations in disease onset and progression (2). In contrast, no alteration of axonal retrograde transport was detected in a SBMA mouse model, strongly suggesting that the impairment seen in ALS is specific (3). Our results strongly indicate altered axonal transport in ALS and provide a new method to closely examine and dissect out the mechanisms underlying axonal transport defects in mouse models of neurodegeneration.

(1) Salinas S et al (2008) Curr Opin Cell Biol, 20, 445-53.
(2) Bilsland L et al., (2010) Proc Natl Acad Sci U S A, 107, 20523-8.
(3) Malik B et al., (2011) Hum Mol Genet. 20, 1776-86.

 

Professor Giampietro Schiavo

Speaker information

Professor Giampietro Schiavo, , Cancer Research UK, London Research Institute, London. Senior Group Leader at the Cancer Research UK London Research Institute and Honorary Professor at University College London

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