Molecular mechanism and function of neuronal ER-phagy

MARIJN KUIJPERS (Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin)
VOLKER HAUCKE (Freie Universität Berlin & Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin)

As neurons are postmitotic cells they need to survive for decades while accumulating damage to proteins and organelles. Neurons have evolved several strategies for removing these damaged materials and to maintain proper neuronal and synaptic function. These strategies include protein degradative pathways consisting of the ubiquitin-proteasome system and lysosomal degradation via autophagy, a process in which parts of the cytoplasm are engulfed by membrane and sent for degradation. In recent years different functions of neuronal autophagy have emerged, including the modulation of neurotransmission and neuron survival. In a recent study (Kuijpers et al. 2021) we highlighted a crucial role of neuronal autophagy in the control of excitatory neurotransmission via the degradation of the axonal Endoplasmic Reticulum (“ER-phagy”). How neuronal ER-phagy is regulated by neuronal activity or other stimuli, which specific protein adaptors control this process, and how defects in ER-phagy may lead to disease(s) are still unknown and will be tackled in this project. We will use cultured mouse and human iPS-derived neurons (iNeurons) as main model systems and utilize proteomic approaches and state-of-the-art imaging techniques to identify and study neuronal ER-phagy adaptors and their roles in synaptic neurotransmission. We are equipped with a variety of imaging setups including electron microscopy, multicolor 3D-gSTED imaging, and correlative STED or confocal/ focussed ion beam milling scanning electron microscopy (FIB-SEM).

3D TEM tomography reconstructions of synaptic boutons showing postsynaptic densities (orange), ER tubules (blue), synaptic vesicles (yellow) and mitochondria (green). Examples are showing a wildtype bouton and an autophagy-deficient (ATG5-KO) bouton with severe ER volume increases. Scale bar, 1 μm.

Kuijpers M, Kochlamazashvili G, Stumpf A, Puchkov D, Swaminathan A, Lucht MT, Krause E, Maritzen T, Schmitz D, Haucke V. (2021) Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum Neuron. 2021 Jan 20;109(2):299-313.

Azarnia Tehran, D.*, Kuijpers, M.*, Haucke., V. (2018) Presynaptic endocytic factors in autophagy and neurodegeneration. Curr. Op. Neurobiol., 48, 153-159

Kononenko, N.L., Claßen, G.A., Kuijpers, M., Puchkov, D., Maritzen, T., Tempes, A., Malik, A.R., Skalecka, A., Bera, S., Jaworski, J., Haucke, V. (2017) Retrograde transport of TrkB-containing autophagosomes via the endocytic adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration. Nature Communications, 8,14819