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Neurobiol Dis. 2019 Mar 28;127:419-431. doi: 10.1016/j.nbd.2019.03.026. [Epub ahead of print]

A mouse model for SPG48 reveals a block of autophagic flux upon disruption of adaptor protein complex five.

Author information

1
Institute of Human Genetics, University Hospital Jena, Friedrich-Schiller-University Jena, Jena 07747, Germany. Electronic address: Mukhran.Khundadze@med.uni-jena.de.
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: Christian.Huebner@med.uni-jena.de.

Abstract

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.

KEYWORDS:

ALR; AP5; Autophagy; Lysosome; SPG48

PMID:
30930081
DOI:
10.1016/j.nbd.2019.03.026

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