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
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.
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
complete list of publications on
Chung KM, Kim H, Roque CG, McCurdy EP, Nguyen TTT, Siegelin MD, Hwang
J-Y, Hengst U. A systemic cell stress signal confers neuronal
resilience toward oxidative stress in a Hedgehog-dependent manner. Cell
Reports. 2022; 41(3):111488
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.
McCurdy EP, Chung KM, Benitez-Agosto CR, Hengst U. Promotion
of axon growth by the secreted end of a transcription factor. Cell
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
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.
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.
Roque CQ, Hengst U. Wimpy Nerves: piRNA Pathway Curbs Axon
Regrowth after Injury. Neuron. 2018; 97(3):477-478
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
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
Batista AFR, Hengst U. Intra-axonal protein
synthesis in development and beyond. International
Journal of Developmental Neuroscience. 2016;55:140-149
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
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
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
Deglincerti A, Liu Y, Colak D, Hengst U, Xu G, Jaffrey SR.
Coupled local translation and degradation regulate growth cone
collapse. Nature Communications.
Baleriola J, Hengst U. Targeting axonal protein synthesis in
neuroregeneration and degeneration. Neurotherapeutics.
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.
on by: Editors'
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
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.
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
and Views by Macara et al.
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
and Views by Lin & Holt
Hengst U, Jaffrey SR. Function and translational regulation of
mRNA in developing axons. Seminars
in Cell and Developmental Biology. 2007;18(2):209-215
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
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
*Wu KY, *Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER,
Jaffrey SR. Local translation of RhoA regulates growth cone collapse.
2005;436(7053):1020-1024 (*equal authorship)
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
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
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
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 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
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.
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.
Michaela (Kayla) Pauers
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.
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.
Individuals with a strong research background in neuroscience,
molecular biology, or cell biology should contact Ulrich to
inquire about open positions and research projects.
We participate in the following graduate programs at Columbia
University Irving Medical Center:
Our home department and institute:
Research in our group is or has been supported by the following
agencies and foundations. We gratefully acknowledge their
Ulrich Hengst, PhD
Columbia University Irving
(for deliveries use: BB12-1212)
650 West 168th Street
New York, NY 10032