Neuronal mRNA trafficking and local translation
Neurons are highly polarized and interactive cells that require precise spatiotemporal regulation of their proteins for proper functioning. To achieve this, neurons have the ability to localize mRNAs and locally synthesize proteins. These processes play key roles in the development, plasticity and maintenance of neurons and dysregulation of these processes are increasingly implicated in neurodegenerative diseases. The main focus of my research group is to understand the molecular mechanisms and functional relevance of mRNA trafficking and local translation in neuronal subcellular compartments in health and disease. In particular, we are interested in the role of the endoplasmic reticulum in regulating mRNA localization and local translation and its role in presynaptic function.
Neurons are morphologically complex and compartmentalized cells with dendrites and axons that establish dynamic connections with many other neurons, often far away from the cell body. The development, efficient functioning and survival of neurons requires careful modulation of their proteome in response to local demands. Recent research has established a crucial role for the correct localization and translation of mRNAs within axons, to allow for spatiotemporal regulation of the neuronal proteome. mRNA trafficking and axonal protein synthesis have been shown to be involved in a multitude of functions and dysregulation of these processes is increasingly implicated in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease. However, how mRNAs are localized and translated in axons remains largely unknown. In addition, the neuronal functions that these processes support, especially in mature neurons, remain unclear.
The main goal of our lab is to acquire a better understanding of the molecular mechanisms and functional consequences of mRNA trafficking and local translation at specific subcellular sites in neurons in health and disease. We recently found that the axonal endoplasmic reticulum (ER) can bind to ribosomes and plays a role in axonal protein synthesis in developing neurons. This raises the exciting idea that the localization and translation of a subset of mRNAs are regulated by the axonal ER and that this is important for neuron development, function and survival.
Our aim is to characterize the proteins and pathways involved in axonal ER-based translation, understand how the axonal ER reticulum regulates mRNA localization and local translation and which neuronal functions it supports. To do so, we use live-cell and super-resolution imaging of neurons combined with genetic engineering tools to visualize and study the axonal ER, ribosomes and mRNA trafficking. In addition, we use proximity-based techniques for visualization and proteomic characterization. Together, this will allow us to understand how and to which extent the axonal ER regulates local translation and which axonal functions it supports in health and disease.
We are currently looking for a PhD candidate to join us from May/June 2023.
Master students are also welcome to apply for an internship in the lab.
Koppers M, Ozkan N, Nguyen HH, Jurriens D, McCaughey J, Stucchi R, Altelaar M, Kapitein LC, Hoogenraad CC, Farias GG. Axonal ER tubules regulate local translation via P180/RRBP1-mediated ribosome interactions. bioRxiv, 2022
Koppers M#, Holt CE#. Receptor-ribosome coupling: a link between extrinsic signals and mRNA translation in neuronal compartments. Annual review of Neuroscience, 2022; 45:41-61
Özkan N, Koppers M, van Soest I, van Harten A, Jurriens D, Liv N, Klumperman J, Kapitein LC, Hoogenraad CC, Farías GG. ER-lysosome contacts at a pre-axonal region regulate axonal lysosome availability. Nature Communications, 2021; 12(1):1-18.
Koppers M, Özkan N, Farías GG. Complex interactions between membrane-bound organelles, biomolecular condensates and the cytoskeleton. Frontiers in Cell and Developmental Biology, 2020; 1661
Koppers M, Cagnetta R, Shigeoka T, Wunderlich LCS, Vallejo-Ramirez P, Qiaojin Lin J, Zhao S, Jakobs MAH, Dwivedy A, Minett MS, Bellon A, Kaminski CF, Harris WA, Flanagan JG, Holt CE. Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons. eLife, 2019 Nov 20;8:e48718.
Shigeoka T, Koppers M, Wong HH, Qiaojin Lin J, Cagnetta R, Dwivedy A, de Freitas Nascimento J, van Tartwijk F, Strohl F, Cioni JM, Schaeffer J, Carrington M, Kaminski CF, Jung H, Harris WA, Holt CE. On-site ribosome remodeling by locally synthesized ribosomal proteins in axons. Cell Reports, 2019 Dec;29(11):3605-3619.
Cioni JM*, Qiaojin Lin J*, Holtermann AV, Koppers M, Jakobs MA, Azizi A, Turner-Bridger B, Shigeoka T, Franze K, Harris WA, Holt CE. Endosomes serve as a platform for mRNA translation in axons and promote mitochondrial and axonal integrity.*Cell*, 2019; Jan; 176(1-2):56-72.e15
Koppers M * , Cioni JM*, Holt CE. Molecular control of local translation in axon development and maintenance. Current Opinion in Neurobiology. 2018 Aug;51:86-94
Koppers M * , Blokhuis AM*, Groen EJ, van den Heuvel DM, Dini Modigliani S, Anink JJ, Fumoto K, van Diggelen F, Snelting A, Sodaar P, Verheijen BM, Demmers JAA, Veldink JH, Aronica E, Bozzoni I, den Hertog J, van den Berg LH, Pasterkamp RJ. Comparative interactomics analysis of different ALS-associated proteins identified converging molecular pathways. Acta Neuropathologica. 2016 Aug;132(2): 175-96.
Koppers M, Blokhuis AM, Westeneng HJ, Terpstra ML, Zundel CAC, Vieira de Sá R, Schellevis RD, Waite AJ, Blake DJ, Veldink JH, van den Berg LH, Pasterkamp RJ. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Annals of Neurology. 2015 Sep; 78(3):426-438.