MicroRNA Transport in Axons of Motor Neurons: Implications in Health and Disease.
Motor neurons are extremely large and polarized cells where the cell body resides in the spinal cord but its far-reaching axon extends to the tips of the toes. In human adults, this can be over a meter long. In order to survive and function properly, the neuron depends on an efficient communication mechanism both within its compartments (cell-body-axon-synapse), as well as with its diverse dynamic microenvironments. This molecular communication process has to be properly timed and located; a signal must be in the right place at the right time. To enable this, the neuron relies on two crucial cellular mechanisms. The first is transport, an active process which transfers organelles, proteins, RNA and other molecules between the cell body and the furthest parts of the axon. The second is local protein synthesis, which translates proteins from RNA at defined locations far from the cell body. Both of these processes are extremely important, and alterations in them can lead to neurodegeneration and diseases such as ALS.
Our lab studies the molecular communication mechanisms essential for motor neuron health. Regulation of local protein synthesis is largely done by microRNAs. MicroRNAs are small, negative regulators of gene expression. The mature microRNA targets mRNA transcripts by base-pairing to a “seed sequence” consisting of six to eight nucleotides, thus preventing their translation into protein. In this manner, gene expression is “silenced”, facilitated by a protein complex known as the RNA-Induced Silencing Complex. Mutations in RNA binding proteins, and in microRNA processing proteins were found to be associated with ALS. Although microRNA biogenesis is relatively well characterized in the cell body, their mechanism of function in the axon is yet to be understood.
In my research, we attempt to understand how microRNA and its regulatory machinery transport and localize in the neuron, and whether this transport is altered in ALS. To this end, we use various state of the art imaging techniques to visualize the microRNA and RNA binding proteins’ dynamics in motoneurons. This approach allows us to track proteins and microRNAs in a living cell, and to see what happens when the cell needs to respond to an induced change in its environment, or in a cell that contains a disease-related mutation.
The questions we attempt to answer in our research help us understand the basic mechanisms of neuronal cell biology. We are hopeful that our discoveries will provide valuable insight into ALS, and perhaps in the not too distant future serve as a basis for novel therapeutic strategies.
Israel Society for Physiology and Pharmacology Annual Meeting, Tel Aviv, Israel 2016
EMBO Conference RNA localization and local translation, Hersonnisos, Crete 2015
Binational meeting on amyotrophic lateral sclerosis Italy – Israel, Tel Aviv 2015
3rd Annual Broad-ISF Cell Circuits Symposium, Jerusalem, Israel 2015
EMBO Workshop “Emerging Concepts of the Neuronal Cytoskeleton”, Puerto Varas, Chile 2015
“Assembly and Disassembly of the Nervous System”, Rehovot, Israel 2015
Israel Society for Neuroscience, 23rd Annual Meeting. Eilat, Israel 2014
EMBO Workshop “Mechanisms of Neuronal Remodelling”, Ein Gedi, Israel 2014
ISN-FENS School on "Local protein synthesis in axons and dendrites", Kolymbari, Crete 2013
Translational Neuroimmunology: A joint meeting of the Israel Society of Neuroimmunology and the Italian Neuroimmunology Association, Tel Aviv, Israel 2009
Gershoni-Emek, N., Ionescu, A., Shani, T., Emek, Y., Ben-Yaakov, K., Gradus-Pery, T., Israelson, A. and Perlson E.
“Mitochondria facilitate axonal RNAi machinery localization and transport via a
stress-sensitive mechanism” (submitted)
Rotem, N., Magen I., Ionescu, A., Gershoni-Emek N., Altman, T., Pasmanik-Chor, M., Willis, D.E., Ben-Dov, I.Z., Hornstein, E., and Perlson, E.
“ALS Along the Axons –Expression of Coding and Noncoding RNA Differs in Axons of ALS models” (Sci Rep, 2017)
Gershoni-Emek, N. Chein, M. and Perlson, E. “Altered Localization of Staufen1 in Amyotrophic Lateral Sclerosis” (RNA Dis, in press 2016)
Moya-Alvarado, G., Gershoni-Emek, N., Perlson, E. and Bronfman, F.C. “Neurodegeneration and Alzheimer's disease. What can proteomics tell us about the Alzheimer's brain?” (Mol Cell Proteomics, 2015)
Gershoni-Emek N., Mazza A., Gradus Pery T., Xiang, X., Li K.W., Sharan R. and Perlson E. “Proteomic Analysis of Dynein interactors in Synaptosomes reveals a role for the RNA-binding Protein Staufen1 in Amyotrophic Lateral Sclerosis” (Mol Cell Proteomics, 2015)
Gershoni-Emek, N., Chein, M., Gluska S., Ionescu A and Perlson E.
“Location, location, location-Amyotrophic Lateral Sclerosis as a spatiotemporal mislocalization disease.” (Invited review in: International Review of Cell & Molecular Biology, 2015)
Gershoni-Emek, N., Zahavi EE., Gluska S., Slobodskoy Y and Perlson, E. “Communication Languages and Agents in Biological Systems.” (Book chapter in Biocommunication: Sign-Mediated Interactions between Cells and Organisms) (World Scientific, 2017)
Lilo, E.#, Wald, S.#, Solmesky L.J., Ben-Yaakov K., Gershoni-Emek N., Gotkine M., Karosis D., Bulvik S., Perlson E. and Weil M.
“Characterization of human sporadic ALS biomarkers in the familial transgenic mSOD1G93A mouse model.” (Human Molecular Genetics, 2013)
Haramati S., Chapnik E.#, Sztainberg H.#, Eilam-Altstadter R., Zwang R., Gershoni N., McGlinn E., Heiser P.W., Wills A., Wirguin I., Rubin L., Misawa H., Tabin C.J., Brown R. Jr., Chen A., Hornstein .E,
“miRNA malfunction causes motor neuron disease.” (PNAS, 2010)
February 2016 - Israel Society for Physiology and Pharmacology Haim Garty Award
May 2015 - Sagol School of Neuroscience and Adams Supercenter for Brain Studies
February 2015 - Constantiner Institute for Molecular Genetics Travel Scholarship (Travel Award)
December 2014 - Prize for Best Swift Oral Poster Presentation, Israel Society for Neuroscience (23rd Annual Meeting)
May 2014 - Sieratzki Prize for Advances in Neuroscience
September 2013 - FENS Travel Scholarship
October 2006 - Graduated summa cum laude, Technion
Research Categories: Cellular/molecular neuroscience