The regulation of cargo sorting along the axonal transport pathway
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The regulation of cargo sorting along the axonal transport pathway
Wed, 15/05/2013 - 14:30 to 15:30
Location:
Speaker:
Dr Giampietro Schiavo
Affiliation:
University College London
Synopsis:
Axonal transport is an essential process for neuron survival and homeostasis. However, this pathway also acts as a portal for the dissemination of virulence factors and pathogens in the nervous system. To investigate the molecular machinery controlling this transport route and the sorting of cargoes undergoing axonal retrograde transport , we have exploited the binding fragment of tetanus toxin (TeNT), and botulinum neurotoxin (BoNT). TeNT is internalised in motor neurons at the neuromuscular junction and is targeted to the soma located in the spinal cord via transport organelles shared with neurotrophins and their receptors Trks and p75NTR. This route requires a specific subset of small GTPases and relies on Rab7 activity for long-range axonal transport powered by cytoplasmic dynein. Mutations of the dynein motor complex and
Rab7 cause motor neuron disease and peripheral neuropathies in human patients, suggesting the possibility that mutations in other components of these pathways may determine and/or predispose these pathologies.
To identify novel players in the regulation of the axonal retrograde transport pathway, we have carried out siRNA screens in embryonal stem cell (ES)-derived motor neurons and primary sensory neurons. Positive and negative regulators of axonal retrograde transport were identified and candidates were validated using secondary screens using axonal transport assays both in vitro and in vivo. Surprisingly, we also found that molecular motors are crucial for intracellular length sensing and growth control in neurons. Hence, siRNA approaches represent a powerful tool to investigate traffic events in neurons and for the discovery of novel physiological functions dependent on this pathway.
Biography:
Dr. Schiavo gained his degree in Chemistry and Pharmaceutical Technology from the University of Padua (Italy) in 1988, followed in 1992 by a PhD in Biological Sciences under the supervision of Prof.
C. Montecucco at the same University. In his Thesis¹ work, he demonstrated that the inhibition of synaptic activity caused by tetanus and botulinum neurotoxins is due to a specific protease activity. Sponsored by an EMBO Fellowship, he then moved to the laboratory of Prof. J. Rothman at the Memorial Sloan Kettering Cancer Center in New York where he investigated novel interactions between the synaptic calcium sensor synaptotagmin and SNARE proteins. In 1997, he established his laboratory at the Cancer Research UK London Research Institute. He is Honorary Professor at University College London, member of EMBO and Fellow of the Academy of Medical Science. His research programme, which focuses on the analysis of axonal transport of virulence factors and neurotrophins, has yielded important results on the role of mutations of motor proteins in neurodegeneration and neurotrophin signalling. He will move to the UCL - Institute of Neurology in 2013.