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.
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.
- PhD, 2003 biochemistry, Basel University, Switzerland
- Postdoctoral Research
2004 – 2009 Weill Medical College of Cornell University, New York, NY, Advisor: Samie R. Jaffrey, MD, PhD
- Graduate Research
1999 – 2003 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland, Advisor: Denis Monard, PhD
- Undergraduate Research
1997 – 1998 Ruhr-University Bochum, Germany, Advisor: Paul Kiefer, MD
2015 – 2019 Irma T. Hirschl Career Scientist Award
2010 – 2012 New Investigator Award of the Alzheimer’s Association
2007 – 2012 NIH Pathway to Independence Award (K99/R00)
2006 – 2007 Postdoctoral Fellowship of the Paralysis Project of America
2001 Travel Award of the Swiss Society for Neuroscience, SfN Meeting
1993 – 1998 Fellow of the German National Academic Foundation (Studienstiftung des deutschen Volkes)
Names of graduate students in the Hengst group are underlined.
Martínez JC, Randolph LK, Iascone DM, Pernice HF, Polleux F, Hengst U. Pum2 Shapes the Transcriptome in Developing Axons through Retention of Target mRNAs in the Cell Body. Neuron. 2019 Dec 4;104(5):931-946.e5.
McCurdy EP, Chung KM, Benitez-Agosto CR, Hengst U. Promotion of Axon Growth by the Secreted End of a Transcription Factor. Cell Rep. 2019 Oct 8;29(2):363-377.e5.
Birdsall V, Martínez JC, Randolph L, Hengst U, Waites CL. Live Imaging of ESCRT Proteins in Microfluidically Isolated Hippocampal Axons. Methods Mol Biol. 2019;1998:117-128.
Walker CA, Randolph LK, Matute C, Alberdi E, Baleriola J, Hengst U. Aβ1-42 triggers the generation of a retrograde signaling complex from sentinel mRNAs in axons. EMBO Rep. 2018 Jul;19(7).
Weyn-Vanhentenryck SM, Feng H, Ustianenko D, Duffié R, Yan Q, Jacko M, Martínez JC, Goodwin M, Zhang X, Hengst U, Lomvardas S, Swanson MS, Zhang C. Precise temporal regulation of alternative splicing during neural development. Nat Commun. 2018 Jun 6;9(1):2189.
Roque CG, Hengst U. Wimpy Nerves: piRNA Pathway Curbs Axon Regrowth after Injury. Neuron. 2018 Feb 7;97(3):477-478.
Batista AFR, Martínez JC, Hengst U. Intra-axonal Synthesis of SNAP25 Is Required for the Formation of Presynaptic Terminals. Cell Rep. 2017 Sep 26;20(13):3085-3098.
Villarin JM, McCurdy EP, Martínez JC, Hengst U. Local synthesis of dynein cofactors matches retrograde transport to acutely changing demands. Nat Commun. 2016 Dec 21;7:13865.
Batista AF, Hengst U. Intra-axonal protein synthesis in development and beyond. Int J Dev Neurosci. 2016 Dec;55:140-149.
Baleriola J, Jean Y, Troy C, Hengst U. Detection of Axonally Localized mRNAs in Brain Sections Using High-Resolution In Situ Hybridization. J Vis Exp. 2015 Jun 17;(100):e52799.
Jean YY, Baleriola J, Fà M, Hengst U, Troy CM. Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus. J Vis Exp. 2015 Jun 17;(100):e52805.
Baleriola J, Hengst U. Targeting axonal protein synthesis in neuroregeneration and degeneration. Neurotherapeutics. 2015 Jan;12(1):57-65.
Baleriola J, Walker CA, Jean YY, Crary JF, Troy CM, Nagy PL, Hengst U. Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell. 2014 Aug 28;158(5):1159-1172.
Gracias NG, Shirkey-Son NJ, Hengst U. Local translation of TC10 is required for membrane expansion during axon outgrowth. Nat Commun. 2014 Mar 25;5:3506.
For a complete list of publications, please visit PubMed.gov