Description of the research breakthrough:
Schuman’s groundbreaking research revealed that proteins critical for neuron communication, plasticity, and memory storage, are produced locally at synapses, the junctions between neurons. With her discovery of local translation during synaptic plasticity, Schuman created the field of neuronal local protein synthesis. Her pioneering work in the neuron, with upwards of 10,000 individual synapses, has shown that it maintains, specializes, and regulates these synaptic compartments through the local translation of mRNAs that code for synaptic proteins. This insight overturns the previous belief that all proteins are made in the cell body and then shipped out to synapses where they function.
In order to study protein synthesis, one needs to identify and visualize the newly synthesized proteins within cells. Schuman and her colleagues invented methods (BONCAT and FUNCAT) that make use of artificial amino acids and click chemistry to label newly synthesized proteins. They showed that these artificial amino acids are recognized and charged by the cell’s endogenous methionyl tRNA synthetase and then incorporated into the nascent polypeptide. This technology enables scientists to tag, identify, and visualize newly synthesized proteins in any cell, tissue, or organ. Schuman labelled and identified newly synthesized proteins from individual cell types, giving the entire suite of technologies a genetically encodable and cell-type specific control.
This platform is now being used across the life sciences to identify proteins that drive cellular changes under normal and altered states. Most recently, her group has optimized the sorting of fluorescent synaptosomes to obtain a deep proteomic profile of the various types of synapses that populate different brain areas, including the cortex, hippocampus, striatum, olfactory bulb, and cerebellum.
Background to the breakthrough:
While a faculty member at California Institute of Technology in the 1990s, Schuman discovered that brain-derived neurotrophic factors (BDNF), one the most important influences on brain growth, also play an important role in driving the plasticity of synapses in adults. In pursuing the mechanisms by which BDNF potentiates synapses, Schuman discovered that this plasticity requires rapid and local protein synthesis. Her 1996 paper opened up an entirely new area: the role of local translation in neuronal function. In this research, she discovered that proteins made locally in dendrites are required for synaptic plasticity, and her team identified the mRNA population present in neuronal dendrites and axons in order to understand protein supply and demand at synapses.
The elements required for protein synthesis within cells include the messenger RNAs (mRNAs). The full potential landscape of dendritic protein synthesis was held back by extremely limited observations on the order of 10 – 100 mRNA molecules in dendrites. In research published in 2012, she demonstrated using RNA sequencing to initially discover more than 2500 mRNA species (“the transcriptome”) present in the neuropil (dendrites and axons) of the hippocampus. Importantly, the large majority of mRNAs that code for synaptic proteins were identified, which suggests that local translation of synaptic proteins is much more the rule than the exception. The next question was to assess the degree to which these transcripts were actually used for protein synthesis.
In 2020, she demonstrated that dendrites use a long-ignored translational format, i.e., they often synthesize proteins using single ribosomes (‘monosomes’), which may optimize limited resources in the small compartments that house synapses. Schuman used ribosome profiling to quantify the level and position of mRNA engagement with ribosomes. In 2021, her work showed that nearly all of the detected mRNAs are translated. Moreover, by comparing the degree of translation in somata vs. axons/dendrites, Schuman showed that local translation, rather than somatic translation, is the dominant source of more than 800 synaptic proteins.
Schuman discovered new mechanisms that allow scientists to understand the logistics of protein synthesis and proteostasis at synapses as well as the importance of local translation in other contexts, including synaptic homeostasis.
Standing:
Schuman is recognized as a pioneer in the field of local translation and has made many key discoveries in neurons that drove the whole field forward as the focus is turning more and more to the mechanisms that drive molecular changes at the level of individual synapses rather than whole neurons.
Schuman’s work has not only launched fundamental discoveries and new technologies in pioneering the field of neuronal local translation, but she has also had an extraordinary influence on the entire field of neuroscience, where the focus is turning more and more to the mechanisms that drive molecular changes at the level of individual synapses rather than whole neurons.
She is a member of EMBO, and the German and U.S. National Academies of Science as well the Royal Society of the United Kingdom. Her research has garnered numerous awards and acclaim, including recently EMBO-FEBS Women in Science Prize in 2022, the Rosenstiel Prize in 2022, the Brain Prize in 2023, and the Körber European Science Prize in 2024.
Biography:
Erin Margaret Schuman was born in California. She did her undergraduate, graduate, and postdoctoral studies at the University of Southern California, Princeton University, and Stanford University respectively. In 1993, she joined the California Institute of Technology’s faculty and was a Howard Hughes Medical Institute (HHMI) investigator from 1997-2009. In 2009, she moved to join the Max Planck Society and currently serves as the managing director at the Max Planck Institute for Brain Research in Frankfurt, Germany. She is also a co-opted Professor of Biology at Goethe University in Frankfurt and professor of Synaptic Function and Plasticity at the Donders Center for Neuroscience and the Faculty of Science of Radboud University in the Netherlands.
Publications:
Kang, H, Schuman, EM. A requirement for local protein synthesis in neurotrophin-induced synaptic plasticity. Science, 273, 1402-1406 (1996).
Hafner, AS, Donlin-Asp, PG, Leitch, B, Herzog, E, Schuman, EM. Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments. Science, 364, (6441), 650. doi: 10.1126/science.aau3644 (2019).
Biever, A, Glock, C, Tushev, G, Ciirdaeva, E, Dalmay, T, Langer, JT, Schuman, EM. Monosomes actively translate synaptic mRNAs in neuronal processes. Science, 367 (6477), eaay 4991. doi: 10.1126/science.aay4991 (2020).
Sun, C, Desch, K, Nassim-Assir, B, Giandomenico, SL, Nemcova, P, Langer, JD, Schuman, EM. An abundance of free regulatory (19 S) proteasome particles regulates neuronal synapses. Science, 380, 811. doi: 10.1126/science.adf2018 (2023).
Van Oostrum, M, Blok, T, Giandomenico, SL, tom Dieck, S, Tushev, G, Fürst, N, Langer, J, Schuman, EM. The proteomic landscape of synaptic diversity across brain regions and cell types. Cell, 186 (24), 5411 - 5427.e23. doi: 10.1101/2023.01.27.525780 (2023).