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

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dc.creatorHirst, Jennifer
dc.creatorEdgar, James R
dc.creatorEsteves, Typhaine
dc.creatorDarios, Frédéric
dc.creatorMadeo, Marianna
dc.creatorChang, Jaerak
dc.creatorRoda, Ricardo H
dc.creatorDürr, Alexandra
dc.creatorAnheim, Mathieu
dc.creatorGellera, Cinzia
dc.creatorLi, Jun
dc.creatorZüchner, Stephan
dc.creatorMariotti, Caterina
dc.creatorStevanin, Giovanni
dc.creatorBlackstone, Craig
dc.creatorKruer, Michael C
dc.creatorRobinson, Margaret S
dc.date2015-06-25T12:53:05Z
dc.date2015-06-25T12:53:05Z
dc.date2015-09-01
dc.date.accessioned2026-08-03T03:49:57Z
dc.descriptionAdaptor 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.
dc.descriptionThis work was supported by the Wellcome Trust (086598; J.H., J.R.E. and M.S.R.), the European Union (OMICS Call, Neuromics project; F.D., A.D., T.E. and G.S.), Verum Foundation (G.S.), Programme d’Investissement d’Avenir (ANR-10-IAIHU-06; F.D., A. D., T.E. and G.S.), ERC starting grant (311149; F.D.), the Intramural Research Program of the NINDS, National Institutes of Health (J.C., R.H.R. and C.B.) and National Institutes of Health grant NS083739 (M.M. and M.C.K.), Doris Duke Foundation (Clinical Scientist Development Award to M.C.K.) and Healthcare Research of the Italian Ministry of Health (C.M. and C.G.). C.G. also received partial research support by AriSLA (NOVALS 2010). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.
dc.descriptionThis is the final version. It was first published by OUP at http://dx.doi.org/10.1093/hmg/ddv220
dc.formatapplication/pdf
dc.identifierHirst et al. Human Molecular Genetics (2015) Vol. 24 Issue 17, pp. 4984-4996. doi: 10.1093/hmg/ddv220
dc.identifier0964-6906
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/248711
dc.identifier1460-2083
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/181368
dc.languageEnglish
dc.languageeng
dc.publisherOxford University Press (OUP)
dc.publisherhttps://doi.org/10.1093/hmg/ddv220
dc.rightsAttribution 2.0 UK: England & Wales
dc.rightshttp://creativecommons.org/licenses/by/2.0/uk/
dc.subjectAdaptor Proteins, Vesicular Transport
dc.subjectAged
dc.subjectEndosomes
dc.subjectFemale
dc.subjectFibroblasts
dc.subjectGene Knockdown Techniques
dc.subjectGenetic Association Studies
dc.subjectHeLa Cells
dc.subjectHumans
dc.subjectLysosomal Storage Diseases
dc.subjectLysosomes
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectMutation
dc.subjectPhenotype
dc.subjectProteins
dc.subjectRNA Interference
dc.titleLoss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease.
dc.typeArticle

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