Project Details
Projekt
Molecular mechanism and function of neuronal ER-phagy
Applicants
Professor Volker Haucke, Ph.D.; Dr. Marijn Kuijpers
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 447288260
Within neuronal networks, electrical signals and chemical neurotransmitters allow for rapid communication from the presynaptic compartment of one neuron to a postsynaptic compartment of another neuron. To support neuronal and synaptic integrity, neurons have evolved strategies for maintaining proper proteostasis and removing damaged proteins. Autophagy is a process in which parts of the cytoplasm are engulfed by membrane and sent for degradation. Work from us and others have not only demonstrated that autophagy is important for neuronal function but also revealed novel molecular links between the machineries for synaptic vesicle (SV) recycling and the autophagy system. However, which neuronal substrates are turned over via the autophagy-lysosomal pathway, how this pathway is controlled and how it is linked to neuronal activity is incompletely understood. To address these crucial questions, we generated knockout mice conditionally lacking the essential autophagy protein ATG5. We discovered that loss of neuronal autophagy causes the selective accumulation of tubular Endoplasmic Reticulum (ER) in axons under physiological conditions, resulting in increased excitatory neurotransmission as a consequence of elevated calcium release from ER stores via ryanodine receptors. We therefore hypothesize that neuronal autophagy controls axonal ER calcium stores to regulate neurotransmission in healthy neurons and in the brain. The overall objective of the proposed project is to understand which specific adaptors control the ER-phagy (i.e. ER degradation by autophagy) process in central nervous system neurons (WP1), how neuronal ER-phagy is regulated by neuronal activity or other stimuli (WP2), and what the physiological roles of ER-phagy are in the post- versus the presynaptic compartment (WP3).
DFG Programme
Research Units
International Connection
Netherlands
