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Work in my laboratory focuses on the role of intra-axonal mRNA translation in development and neurodegenerative disorders.
Traditionally, protein synthesis has been considered to occur exclusively in the cell body, but in highly polarized cells such as neurons some mRNAs are selectively transported to the periphery. Over the last couple of years, several axonal mRNAs as well as stimuli that trigger their translation have been described: the guidance cue Semphorin3A causes growth cone collapse in sensory neurons by triggering the local synthesis of RhoA; the mRNA for the transcription factor CREB is locally translated in response to NGF, and CREB then translocates to the nucleus and supports neuronal survival. We also found that netrin-1 and NGF trigger axonal elongation via the local translation of Par3, a key component of the PAR polarity complex. Despite increasing evidence for the existence of local translation in many questions remain unanswered: What is the in vivo relevance of local translation? Why are some proteins locally translated? What is the role of local translation in neurodegenerative disorders?
In order to address these questions we are currently working on several closely related projects:
• Local protein synthesis and neurodegeneration. Intra-axonal mRNA translation is necessary for axon development and regeneration. Additionally, various neurodegenerative disorders are linked to axonally localized mRNAs, axon transport or potentially the intra-axonal protein translation machinery. We are studying the relevance of axonal protein synthesis for neurodegeneration on the examples of Alzheimer’s disease and hereditary spastic paraplegia.
• Creation of an in vivo model in which a specific mRNA that is normally found and translated in axons can be restricted to the cell body. This model will allow us to study the role of local translation during development as well as in the mature and aging nervous system.
• The post-translational modification of locally synthesized proteins. The need for local translation is often attributed to the extreme distances between the cell body and the distal ends of axons. However, it remains puzzling why this distance would be a problem for some but not other proteins. In fact, most axonal proteins are synthesized in the cell body and retrogradely transported to the periphery. Further, even for proteins whose transcripts are localized to axons the majority of the axonal protein mass is cell body-derived and only a small fraction is locally translated. A possible explanation for this observation might be that axonally synthesized proteins are functionally distinct from proteins transported from the cell body. A likely source for a functional difference could be distinct post-translation modifications, such as glycosylation, of axonally synthesized proteins.
