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
Hum. Mol. Genet.. 2015-06-17; 24(17): 4984-4996
DOI: 10.1093/hmg/ddv220

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

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

Hirst J(1), Edgar JR(2), Esteves T(3), Darios F(4), Madeo M(5), Chang J(6), Roda
RH(6), Dürr A(7), Anheim M(8), Gellera C(9), Li J(10), Züchner S(11), Mariotti
C(9), Stevanin G(12), Blackstone C(6), Kruer MC(13), Robinson MS(2).

Author information:
(1)Cambridge Institute for Medical Research, University of Cambridge, Cambridge,
UK, .
(2)Cambridge Institute for Medical Research, University of Cambridge, Cambridge,
UK.
(3)Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR
S_1127, Institut du Cerveau et de la Moelle épinière, Paris F-75013, France,
Ecole Pratique des Hautes Etudes, Paris F-75014, France.
(4)Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR
S_1127, Institut du Cerveau et de la Moelle épinière, Paris F-75013, France.
(5)Sanford Children’s Health Research Center, Barrow Neurological Institute and
Ronald A. Matricaria Institute of Molecular Medicine, Phoenix Children’s
Hospital, Sioux Falls, SD, USA.
(6)Cell Biology Section, Neurogenetics Branch, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
(7)Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR
S_1127, Institut du Cerveau et de la Moelle épinière, Paris F-75013, France,
APHP, Department of Genetics, Pitié-Salpêtrière Hospital, Paris F-75013, France.
(8)Département de Neurologie, Hôpital de Hautepierre, Strasbourg, France.
(9)Genetics of Neurodegenerative and Metabolic Diseases Unit, IRCCS-Fondazione
Istituto Neurologico Carlo Besta, Milan 20133, Italy.
(10)Department of Neurology, Vanderbilt Brain Institute and Centre for Human
Genetics Research, Vanderbilt University School of Medicine, 1161 21th Avenue
South, Nashville, TN, USA.
(11)Department of Human Genetics and Hussman Institute for Human Genomics, Miller
School of Medicine, University of Miami, Miami, FL, USA.
(12)Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR
S_1127, Institut du Cerveau et de la Moelle épinière, Paris F-75013, France,
Ecole Pratique des Hautes Etudes, Paris F-75014, France, APHP, Department of
Genetics, Pitié-Salpêtrière Hospital, Paris F-75013, France.
(13)Sanford Children’s Health Research Center, Barrow Neurological Institute and
Ronald A. Matricaria Institute of Molecular Medicine, Phoenix Children’s
Hospital, Sioux Falls, SD, USA, Barrow Neurological Institute & Ronald A.
Matricaria Institute for Molecular Medicine, Phoenix Children’s Hospital,
Phoenix, AZ and Department of Child Health, University of Arizona College of
Medicine, Phoenix, AZ.

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.

© The Author 2015. Published by Oxford University Press.

DOI: 10.1093/hmg/ddv220
PMCID: PMC4527494
PMID: 26085577 [Indexed for MEDLINE]

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