Ulrich Hengst, PhD

Intra-axonal Protein Synthesis

Regulation of Gene Expression on the Subcellular Scale

Neurons are the cells with the most extreme morphological polarization, with distances between the periphery and the neuronal cell bodies ranging from millimeters to several feet. This extreme architectural polarization is mirrored in the existence of functionally distinct subcellular compartments: dendrites, axon, and soma. Spatially restricted protein expression within these compartments is crucial for the establishment and maintenance of neuronal morphology and function. Alterations of polarized protein expression can cause or contribute to the pathogenesis of a wide variety of disorders.

Traditionally, protein synthesis is considered to occur in the cell body immediately following transcription, but in many cells including neurons some mRNAs are transported to the periphery and only translated in response to specific signals. Despite increasing evidence for the existence of local translation in developing axons many questions remain unanswered: Why is local synthesis of some proteins advantageous over transport from the cell body?  What is the role of intra-axonal translation after development?

Our laboratory studies the physiological role of intra-axonal translation during development as well as the possible role of local protein synthesis during neurodegenerative disorders, especially Alzheimer's disease.

Local Translation in Developing and Regenerating Axons

During the development of the nervous system guidance cues direct the growing axons to their cognate synaptic targets. Local protein synthesis has been recognized as a pivotal mechanism for  axons to react in a spatially and temporally acute manner to extracellular signals. Similarily, after nerve injury a subset of mRNAs is rapidly recruited into the axons and locally translated. So far, most  localized mRNAs identified as targets of extracellular signals enode components or regulators of the axonal cytoskeleton. We are interested in the question whether other structural processes in developing and regenerating axons are controlled by local protein synthesis as well. We are employing in vitro in vivo approaches to understand how locally translated mRNAs are co-regulated to support axonal elongation.

Neurodegeneration

In contrast to the developmental period, axons in the mature nervous system seem to be translationally inactive but rapidly reactivate the local translational machinery following nerve injury. Currently, the relevance of intra-axonal protein synthesis in the context of neurodegenerative diseases remains entirely unknown. We seek to understand whether and how the axonal proteome and transcriptome are changed under neurodegenerative conditions such as Alzheimer's disease.