Molecular Dynamics of the Synapse

Neuronal synapses have two fundamental functions in the brain: (1) information flow through neural circuits that is necessary to produce complex behaviour and (2) activity-driven synaptic remodelling for memory storage. Despite this predominant role in long-term information storage, synapses are composed of molecules (i.e. RNA and proteins) with half-lives several order of magnitude shorter than memories themselves^1–3. Indeed, in a matter of days the brain’s principal components are fully turned over while memories can be stored for several decades. Understanding how neurons manage to replace these unstable components and retain the information encoded in synapses is one of neuroscience’s greatest challenges.

Protein targeting to specific subcellular compartments is a shared feature of cells, but neurons take the challenge to its apogee. In the mouse brain it is common for dendrites to extend over hundreds of micrometers and for axons to be tens of millimeters long. Recently I have demonstrated that local production of proteins is a shared feature of both side of the synapses⁴. This finding is driving a paradigm shift in our understanding of synaptic function. Investigating the dynamics of the synaptic proteome homeostasis is fundamental for our deeper understanding of the synapse operation in healthy and diseased brains.

Using state-of-the-art methods such as metabolic labeling of nascent proteomes and super-resolution microscopy techniques as well as omics-approaches I want to characterize and investigate synapses -with a strong focus on the presynapse- transcriptome and proteome dynamics. Functional and/or structural defects in mature axons are major early contributors to the genesis, progression, and symptomatology of many neurodegenerative diseases (NDs)⁵. However, what triggers the transition from healthy aging to NDs remains elusive. Studying protein synthesis in presynaptic terminals will advance our basic understanding of synaptic function and plasticity and will provide critical insights into the early mechanisms underlying NDs.

1. _{Cohen, L. D. et al. Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance. PLoS One 8, (2013).}
2. _{Dörrbaum, A. R., Kochen, L., Langer, J. D. & Schuman, E. M. Local and global influences on protein turnover in neurons and glia. Elife 7, 1–24 (2018).}
3. _{Fornasiero, E. F. et al. Precisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions. Nat. Commun. 9, (2018).}
4. _{Hafner, A.-S., Donlin-Asp, P. G., Leitch, B., Herzog, E. & Schuman, E. M. Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments. Science. 364, 6441 (2019).}
5. _{Salvadores, N., Sanhueza, M., Manque, P. & Court, F. A. Axonal degeneration during aging and its functional role in neurodegenerative disorders. Front. Neurosci. 11, (2017).}