Project Details
Projekt
Molecular mechanism and function of neuronal autophagy
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 447288260
Neuronal integrity depends on basal autophagy, likely because misfolded proteins and damaged organelles cannot be diluted through cell division and will thus accumulate in neurites and within the soma. A key event in the early steps of autophagosome formation is the conjugation of members of the ubiquitin-like ATG8 family that includes in vertebrates the LC3 and GABARAP (gamma-aminobutyric-acid-receptor-associated protein) subfamilies (e.g. LC3A, LC3B, GABARAP, GABARAPL1, GABARAPL2, while LC3C encodes a pseudogene), to phosphatidylethanolamine (PE) in precursor membranes. Research within RP05 has unraveled a crucial role of ATG5-dependent neuronal autophagy in the control of excitatory neurotransmission. This mechanism involves the accumulation of tubular ER membranes in axons (but not in dendrites or somata), resulting in the dysregulation of axonal calcium homeostasis and large conductance potassium-channel (BKCa)-dependent alterations in the AP waveform. Moreover, we have found evidence for a distinctive localization, interactome, and, likely, function of the various isoforms of the LC3/GABARAP family. We therefore propose that distinct isoforms of the LC3/ GABARAP protein family contribute to the functional diversity and substrate specificity of neuronal autophagy via ATG5-dependent and ATG5-independent mechanisms. Specifically, we aim to unravel the physiological functions and cargo protein content of autophagosomes comprising GABARAP L2 and the related GABARAP/ GABARAPL1 proteins. We will address this hypothesis in two work packages using combined cutting-edge technologies ranging from organelle proteomics to functional optical and electrophysiological recordings in genome engineered neuronal human and mouse models. We predict this project to yield fundamental insights into the isoform-specific functions of LC3/GABARAP proteins and, thereby, into the functional diversity and substrate specificity of neuronal autophagy via ATG5-dependent and ATG5-independent mechanisms.
DFG Programme
Research Units
