Intra-axonal protein synthesis

See my work

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

complete list of publications on PubMed link or Google Scholar link


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
EMBO reports link

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
NPG link

Roque CQ, Hengst U. Wimpy Nerves: piRNA Pathway Curbs Axon Regrowth after Injury. Neuron. 2018; 97(3):477-478
Cell Reports link


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):3085-3098
Cell Reports link


2016

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

NPG link

Batista AFR, Hengst U. Intra-axonal protein synthesis in development and beyond. International Journal of Developmental Neuroscience. 2016;55:140-149

Elsevier link

Li S, Fu J, Lu C, Mapara MY, Raza S, Hengst U, Lentzsch S. Elevated Translation Initiation Factor eIF4E is an Attractive Therapeutic Target in Multiple Myeloma. Molecular Cancer Therapeutics. 2016;15(4):711-719

Molecular Cancer Therapeutics link

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

JoVE link

Jean YY, Baleriola J, Fa' M, Hengst U, Troy CM. Stereotaxic infusion of oligomeric amyloid-beta into the mouse hippocampus. Journal of Visualized Experiments. 2015(100):e52805

JoVE link

Deglincerti A, Liu Y, Colak D, Hengst U, Xu G, Jaffrey SR. Coupled local translation and degradation regulate growth cone collapse. Nature Communications. 2015;6:6888

NPG link

Baleriola J, Hengst U. Targeting axonal protein synthesis in neuroregeneration and degeneration. Neurotherapeutics. 2015;12(1):57-65

SpringerLink

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):1159-1172

Cell linkReported on by: Alzheimer ForumEditors' Choice in: Science Signaling  Commentary in: CNS & Neurological Disorders - Drug Targets

Gracias NG, Shirkey-Son NJ, Hengst U. Local translation of TC10 is required for membrane expansion during axon outgrowth. Nature Communications. 2014;5:3506

NPG link

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

NPG link

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

NCB linkNews 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):149-159

NCB linkF1000News and Views by Lin & Holt

2007

Hengst U, Jaffrey SR. Function and translational regulation of mRNA in developing axons. Seminars in Cell and Developmental Biology. 2007;18(2):209-215

Elsevier

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

NNeuro link

Hengst U, Cox LJ, Macosko EZ, Jaffrey SR. Functional and selective RNA interference in developing axons and growth cones. Journal of Neuroscience. 2006;26(21):5727-5732

JNeuro linkF1000

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)

Nature linkF1000

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

JNeuro link

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

PNAS link

Hengst U, Albrecht H, Hess D, Monard D. The phosphatidylethanolamine-binding protein is the prototype of a novel family of serine protease inhibitors. Journal of Biological Chemistry. 2001;276(1):535-540

JBC link

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

SpringLink

UHengstUlrich 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


ClaudioCláudio 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.

Graduate Students


JoséJosé C. Martínez

José received his undergraduate degree in Biochemistry and Neuroscience from the University of Miami. Currently, he is applying computational and molecular techniques to dissect the sub-cellular control of gene expression.


LisaLisa K. Randolph

Lisa received her undergraduate degree in Neuroscience from Vassar College. She is currently investigating axonal regeneration and changes in gene expression related to localized neurodegenerative stimuli. 




EthanEthan P. McCurdy

Ethan received his Bachelor’s degree in Chemistry from Auburn University. He is investigating how local synthesis events influence cause transcriptional changes in neurodegeneration.


Staff


Joanna E. Merriam, MD/PhD

Associate Research Scientist

Alumni


Andreia Filipa Rodrigues Batista


Chandler A. Walker, PhD

Jimena Baleriola Gomez De Pablos, PhD


Joseph M. Villarin, PhD


Neilia G. Gracias, PhD

Huray Basar

Nicole J. Shirkey-Son, PhD

Joan Claire Zimmeck, M.S.

Ahra Joh

Eitan Shimko

lab scene

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.