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

Jennifer Hirst, James R. Edgar, Typhaine Esteves, Frédéric Darios, Marianna Madeo, Jaerak Chang, Ricardo H. Roda, Alexandra Dürr, Mathieu Anheim, Cinzia Gellera, Jun Li, Stephan Züchner, Caterina Mariotti, Giovanni Stevanin, Craig Blackstone, Michael C. Kruer, Margaret S. Robinson

Research output: Contribution to journalArticle

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 showthat 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 formarkers 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-5ζ. 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.

Original languageEnglish
Pages (from-to)4984-4996
Number of pages13
JournalHuman Molecular Genetics
Volume24
Issue number17
DOIs
Publication statusPublished - 2015

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Hirst, J., Edgar, J. R., Esteves, T., Darios, F., Madeo, M., Chang, J., Roda, R. H., Dürr, A., Anheim, M., Gellera, C., Li, J., Züchner, S., Mariotti, C., Stevanin, G., Blackstone, C., Kruer, M. C., & Robinson, M. S. (2015). Loss of AP-5 results in accumulation of aberrant endolysosomes: Defining a new type of lysosomal storage disease. Human Molecular Genetics, 24(17), 4984-4996. https://doi.org/10.1093/hmg/ddv220