Chaperone-mediated autophagy in neuronal dendrites utilizes activity-dependent lysosomal exocytosis for protein disposal
Katarzyna M. Grochowska,
Marit Sperveslage,
Rajeev Raman,
Antonio V. Failla,
Dawid Głów,
Christian Schulze,
Laura Laprell,
Boris Fehse,
Michael R. Kreutz
Affiliations
Katarzyna M. Grochowska
Leibniz Group “Dendritic Organelles and Synaptic Function,” Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; Research Group Neuroplasticity, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany; Corresponding author
Marit Sperveslage
Leibniz Group “Dendritic Organelles and Synaptic Function,” Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; Research Group Neuroplasticity, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany
Rajeev Raman
Research Group Neuroplasticity, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany
Antonio V. Failla
UKE Microscopic Imaging Facility (umif), University Medical Center Eppendorf, 20251 Hamburg, Germany
Dawid Głów
Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf (UKE), 20246 Hamburg, Germany
Christian Schulze
Institute of Synaptic Physiology, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Laura Laprell
Institute of Synaptic Physiology, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Boris Fehse
Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf (UKE), 20246 Hamburg, Germany
Michael R. Kreutz
Leibniz Group “Dendritic Organelles and Synaptic Function,” Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; Research Group Neuroplasticity, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany; Center for Behavioral Brain Sciences, Otto von Guericke University, 39120 Magdeburg, Germany; German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany; Corresponding author
Summary: The complex morphology of neurons poses a challenge for proteostasis because the majority of lysosomal degradation machinery is present in the cell soma. In recent years, however, mature lysosomes were identified in dendrites, and a fraction of those appear to fuse with the plasma membrane and release their content to the extracellular space. Here, we report that dendritic lysosomes are heterogeneous in their composition and that only those containing lysosome-associated membrane protein (LAMP) 2A and 2B fuse with the membrane and exhibit activity-dependent motility. Exocytotic lysosomes dock in close proximity to GluN2B-containing N-methyl-D-aspartate-receptors (NMDAR) via an association of LAMP2B to the membrane-associated guanylate kinase family member SAP102/Dlg3. NMDAR-activation decreases lysosome motility and promotes membrane fusion. We find that chaperone-mediated autophagy is a supplier of content that is released to the extracellular space via lysosome exocytosis. This mechanism enables local disposal of aggregation-prone proteins like TDP-43 and huntingtin.
