Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease

Hum Mol Genet. 2015 Sep 1;24(17):4984-96. doi: 10.1093/hmg/ddv220. Epub 2015 Jun 17.

Abstract

Adaptor proteins (AP 1-5) are heterotetrameric complexes that facilitate specialized cargo sorting in vesicular-mediated trafficking. Mutations in AP5Z1, encoding a subunit of the AP-5 complex, have been reported to cause hereditary spastic paraplegia (HSP), although their impact at the cellular level has not been assessed. Here we characterize three independent fibroblast lines derived from skin biopsies of patients harbouring nonsense mutations in AP5Z1 and presenting with spastic paraplegia accompanied by neuropathy, parkinsonism and/or cognitive impairment. In all three patient-derived lines, we show that there is complete loss of AP-5 ζ protein and a reduction in the associated AP-5 µ5 protein. Using ultrastructural analysis, we show that these patient-derived lines consistently exhibit abundant multilamellar structures that are positive for markers of endolysosomes and are filled with aberrant storage material organized as exaggerated multilamellar whorls, striated belts and 'fingerprint bodies'. This phenotype can be replicated in a HeLa cell culture model by siRNA knockdown of AP-5 ζ. The cellular phenotype bears striking resemblance to features described in a number of lysosomal storage diseases (LSDs). Collectively, these findings reveal an emerging picture of the role of AP-5 in endosomal and lysosomal homeostasis, illuminates a potential pathomechanism that is relevant to the role of AP-5 in neurons and expands the understanding of recessive HSPs. Moreover, the resulting accumulation of storage material in endolysosomes leads us to propose that AP-5 deficiency represents a new type of LSDs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics*
  • Aged
  • Endosomes / metabolism*
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / ultrastructure
  • Gene Knockdown Techniques
  • Genetic Association Studies
  • HeLa Cells
  • Humans
  • Lysosomal Storage Diseases / genetics*
  • Lysosomal Storage Diseases / metabolism*
  • Lysosomes / metabolism*
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Proteins / genetics
  • Proteins / metabolism
  • RNA Interference

Substances

  • AP5B1 protein, human
  • Adaptor Proteins, Vesicular Transport
  • Proteins
  • SPG11 protein, human