Intra-axonal protein synthesis
Local protein synthesis in neurons
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 (primary rodent neurons) and in vivo approaches to understand how locally translated mRNAs are co-regulated to support axonal elongation.Neurodegeneration
We have uncovered a crucial role for intra-axonal synthesis in the long-range transmission of neurogeneration in Alzheimer's disease. Exposure of axons to oligomeric β-amyloid (1-42) leads to a rapid recruitment of mRNAs into axons and activation of intra-axonal protein synthesis in the mature central nervous system. The transcription factor ATF4 is locally synthesized and retrogradely transported to the neuronal cell body where it changes gene expression in a pathogenic manner, leading to cell death. Prevention of axonal ATF4 synthesis is sufficient to rescue neurons from neurodegeneration induced by axonally sensed Aβ1-42, both in vitro and in vivo. Our results suggest that interference with intra-axonal protein synthesis might be a potential strategy for the treatment of neurodegenerative disorders, including Alzheimer's disease.Publications
or 
2019
Martinez 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;104(5):931-946
McCurdy EP, Chung KM, Benitez-Agosto CR, Hengst U. Promotion of axon growth by the secreted end of a transcription factor. Cell Reports. 2019;29(2):363-377
Birdsall V, Martinez JC, Randolph L, Hengst U, Waites CL. Live Imaging of ESCRT Proteins in Microfluidically Isolated Hippocampal Axons. Methods in Molecular Biology. 2019;1998:117–128
2018
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 Reports. 2018;e45435
Weyn-Vanhentenryck SM, Feng H, Ustianenko D, Yan Q, 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. Nature Communications. 2018;9(1):2189
Roque CQ, Hengst U. Wimpy Nerves: piRNA Pathway Curbs Axon Regrowth after Injury. Neuron. 2018; 97(3):477-478
2017
Batista AFR, Martínez JC, Hengst U. Intra-axonal synthesis of SNAP25 is required for the formation of presynaptic terminals. Cell Reports. 2017; 20(13):3085-30982016
Villarin JM, McCurdy EP, Martinez JC, Hengst U. Local synthesis of dynein cofactors matches retrograde transport to acutely changing demands. Nature Communications. 2016;7:13865
2015
Baleriola J, Jean YY, Troy CM, Hengst U. Detection of axonally localized mRNAs in brain sections using high-resolution in situ hybridization. Journal of Visualized Experiments. 2015(100):e52799
2014
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;158(5):1159-1172Reported
on by: 
Editors'
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Commentary in: CNS
& Neurological Disorders - Drug Targets
2012
Walker BA, Hengst U, Kim HJ, Jeon NL, Schmidt EF, Heintz N, Milner TA, Jaffrey SR. Reprogramming axonal behavior by axon-specific viral transduction. Gene Therapy. 2012;19(9):947-955
2009
Hengst U, Deglincerti A, Kim HJ, Jeon NL, Jaffrey SR. Axonal elongation triggered by stimulus-induced local translation of a polarity complex protein. Nature Cell Biology. 2009;11(8):1024-1030
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and Views by Macara et al.
2008
Cox LJ, Hengst U, Gurskaya NG, Lukyanov KA, Jaffrey SR. Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival. Nature Cell Biology. 2008;10(2):149-1592007
Hengst U, Jaffrey SR. Function and translational regulation of mRNA in developing axons. Seminars in Cell and Developmental Biology. 2007;18(2):209-215
2006
Wu KY, Zippin JH, Huron DR, Kamenetsky M, Hengst U, Buck J, Levin LR, Jaffrey SR. Soluble adenylyl cyclase is required for netrin-1 signaling in nerve growth cones. Nature Neuroscience. 2006;9(10):1257-1264
2005
*Wu KY, *Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, Jaffrey SR. Local translation of RhoA regulates growth cone collapse. Nature. 2005;436(7053):1020-1024 (*equal authorship)
2004
Kvajo M, Albrecht H, Meins M, Hengst U, Troncoso E, Lefort S, Kiss JZ, Petersen CC, Monard D. Regulation of brain proteolytic activity is necessary for the in vivo function of NMDA receptors. Journal of Neuroscience. 2004;24(43):9734-9743
2001
Murer V, Spetz JF, Hengst U, Altrogge LM, de Agostini A, Monard D. Male fertility defects in mice lacking the serine protease inhibitor protease nexin-1. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(6):3029-3033
2000
Hengst U, Kiefer P. Domains of human respiratory syncytial virus P protein essential for homodimerization and for binding to N and NS1 protein. Virus Genes. 2000;20(3):221-225
Ulrich
Hengst, PhD
Ulrich did his undergraduate work at the
Ruhr Universität Bochum, Germany, and received his Dr. phil. in
biochemistry from the Universität Basel, Switzerland, while working
at the Friedrich Miescher Institute in the group of Dr. Denis
Monard. He then joined the group of Dr. Samie R. Jaffrey at
Weill Cornell Medical College, New York, NY, for his postdoctoral
training. In 2009, he started as an Assistant Professor at Columbia
University Medical Center and got promoted to Associate Professor in
2016.
Postdocs
Cláudio
Gouveia Roque, PhD
Cláudio joined the group after receiving
his PhD from the University of Coimbra, Portugal, for his graduate
studies performed in the group of Dr. Christine Holt in Cambridge,
UK. He is leading our research on the function of axonally derived
nuclear complexes in the context of Alzheimer's disease.
Radhika
Jagannathan, MD/PhD
Radhika received her S.B. from
MIT and her MD/PhD from the Washington University in St.
Louis, followed by her residency in neurology at Weill
Cornell Medicine. Currently, she is a clinical fellow in
neurology at CUIMC and engaged in research aimed at
characterizing shared pathogenic signaling pathways in AD
and PD/LBD.
Krystal
Herline-Killian, PhD
Krystal received her
undergraduate degree in Biology from Augusta University then
did her PhD at New York University in Thomas Wisniewski’s
laboratory. Currently, she is investigating how protein
aggregates associated with Alzheimer’s disease lead to
widespread transcriptional changes.
Kyung
Min Chung, PhD
Kyung Min received his BS
degrees in Psychology and General Biology from the
University of Washington and a Master’s degree in
Neuroscience from Tulane University, before completing his
PhD from Daegu Gyeongbuk Institute of Science and
Technology (DGIST) in South Korea. Currently, he is
studying in Hedgehog signaling in neurodegenerative
disorders.
Graduate Students
Lisa
K. Randolph
We are always delighted to hear from highly motivated, enthusiastic individuals interested in joining our research team. Please contact Ulrich for the latest information about our research projects.
Rotations
We participate in the Integrated, the Neurobiology, and the Pathology PhD programs at Columbia University Irving Medical Center. Current graduate students are always welcome to contact us to discuss potential rotation projects.Prospective Graduate Students
Undergraduates interested in pursuing their PhD studies in our laboratory have to apply directly to a graduate program at CUIMC.Postdocs
Individuals with a strong research background in neuroscience, molecular biology, or cell biology should contact Ulrich to inquire about open positions and research projects.Links
We participate in the following graduate programs at Columbia University Irving Medical Center:
Pathobiology
and Molecular Medicine
Neurobiology and Behavior
Integrated Program in Cellular, Molecular and Biomedical Studies
MD/PhD Program
Neurobiology and Behavior
Integrated Program in Cellular, Molecular and Biomedical Studies
MD/PhD Program
Our home department and institute:
Research in our group is or has been supported by the following agencies and foundations. We gratefully acknowledge their generous support!
The Irma T. Hirschl Trust
Ulrich Hengst, PhD
Columbia University Irving
Medical Center
BB12-1210A
(for deliveries use: BB12-1212)
650 West 168th Street
New York, NY 10032
phone: 1-212-305-9334
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