Disease mechanism described
The adaptor protein complex (AP5) function in SPG48 HSP neurons is impaired with trafficking, structural and waste removal defects found in these cells, finally resulting in axon degeneration.
Hereditary spastic paraplegia is a spastic gait disorder that arises from degeneration of corticospinal axons. The subtype SPG48 is associated with mutations in the zeta subunit of the adaptor protein complex five (AP5). AP5 function and the pathophysiology of SPG48 are only poorly understood.
Here, we report an AP5 zeta knockout mouse, which shows an age-dependent degeneration of corticospinal axons. Our analysis of knockout fibroblasts supports a trafficking defect from late endosomes to the transGolgi network and reveals a structural defect of the Golgi. We further show that both autophagic flux and the recycling of lysosomes from autolysosomes were impaired in knockout cells.
In vivo, we observe an increase of autophagosomes and autolysosomes and, at later stages, the accumulation of intracellular waste in neurons. Taken together, we propose that loss of AP5 function blocks autophagy and thus leads to the aberrant accumulation of autophagic cargo, which finally results in axon degeneration.
SOURCE: Neurobiol Dis. 2019 Mar 28;127:419-431. doi: 10.1016/j.nbd.2019.03.026. [Epub ahead of print] PMID: 30930081 Copyright © 2019 Elsevier Inc. All rights reserved.
A mouse model for SPG48 reveals a block of autophagic flux upon disruption of adaptor protein complex five.
Khundadze M1, Ribaudo F2, Hussain A2, Rosentreter J2, Nietzsche S3, Thelen M4, Winter D4, Hoffmann B5, Afzal MA2, Hermann T2, de Heus C6, Piskor EM7, Kosan C7, Franzka P2, von Kleist L8, Stauber T8, Klumperman J6, Damme M9, Proikas-Cezanne T10, Hübner CA11.
1 Institute of Human Genetics, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07747, Germany. Electronic address: [email protected]
2 Institute of Human Genetics, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07747, Germany.
3 Electron Microscopy Center, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07743, Germany.
4 Institute for Biochemistry and Molecular Biology, University of Bonn, Bonn 53115, Germany.
5 Biomolecular Photonics Group, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07743, Germany.
6 Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584, Netherlands.
7 Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Jena 07743, Germany.
8 Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin 14195, Germany.
9 Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel 24118, Germany.
10 Department of Molecular Biology, Eberhard Karls University Tübingen, Tübingen 72076, Germany.
11 Institute of Human Genetics, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07747, Germany. Electronic address: [email protected]