2. Academic Validation
  3. Chaperone-mediated autophagy in neuronal dendrites utilizes activity-dependent lysosomal exocytosis for protein disposal

Chaperone-mediated autophagy in neuronal dendrites utilizes activity-dependent lysosomal exocytosis for protein disposal

  • Cell Rep. 2023 Aug 16;42(8):112998. doi: 10.1016/j.celrep.2023.112998.
Katarzyna M Grochowska 1,  Marit Sperveslage 2,  Rajeev Raman 3,  Antonio V Failla 4,  Dawid Głów 5,  Christian Schulze 6,  Laura Laprell 6,  Boris Fehse 5,  Michael R Kreutz 7
Affiliations

Affiliations

  • 1 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. Electronic address: katarzyna.grochowska@zmnh.uni-hamburg.de.
  • 2 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.
  • 3 Research Group Neuroplasticity, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany.
  • 4 UKE Microscopic Imaging Facility (umif), University Medical Center Eppendorf, 20251 Hamburg, Germany.
  • 5 Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Centre Hamburg-Eppendorf (UKE), 20246 Hamburg, Germany.
  • 6 Institute of Synaptic Physiology, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
  • 7 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. Electronic address: michael.kreutz@zmnh.uni-hamburg.de.
PMID: 37590146 DOI: 10.1016/j.celrep.2023.112998
Abstract

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.

Keywords

CMA; CP: Cell biology; CP: Neuroscience; GluN2B NMDAR; LAMP2; SAP102; dendrites; exocytosis; lysosomes.

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