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

Neurobiol Dis. 2019 Jul;127:419-431. doi: 10.1016/j.nbd.2019.03.026. Epub 2019 Mar 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autophagy / physiology*
  • Disease Models, Animal
  • Lysosomes / metabolism
  • Lysosomes / pathology
  • Mice
  • Mice, Knockout
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neurons / metabolism*
  • Neurons / pathology
  • Pyramidal Tracts / metabolism
  • Pyramidal Tracts / pathology
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / metabolism*


  • Adaptor Proteins, Signal Transducing