Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations

Ning Zhang; Yaroslav Tsybovsky; Alexander V Kolesnikov; Malgorzata Rozanowska; Malgorzata Swider; Sharon B Schwartz; Edwin M Stone; Grazyna Palczewska; Akiko Maeda; Vladimir J Kefalov; Samuel G Jacobson; Artur V Cideciyan; Krzysztof Palczewski

doi:10.1093/hmg/ddv073

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Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations

Journal article

Open access

Peer reviewed

Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations

Ning Zhang, Yaroslav Tsybovsky, Alexander V Kolesnikov, Malgorzata Rozanowska, Malgorzata Swider, Sharon B Schwartz, Edwin M Stone, Grazyna Palczewska, Akiko Maeda, Vladimir J Kefalov, …

Human molecular genetics, Vol.24(11), pp.3220-3237

06/01/2015

DOI: 10.1093/hmg/ddv073

PMCID: PMC4424957

PMID: 25712131

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Abstract

Mutations in the ABCA4 gene are a common cause of autosomal recessive retinal degeneration. All mouse models to date are based on knockouts of Abca4, even though the disease is often caused by missense mutations such as the complex allele L541P;A1038V (PV). We now show that the PV mutation causes severe human disease whereas the V mutation alone causes mild disease. Mutant ABCA4 proteins expressed heterologously in mammalian cells retained normal cellular localization. However, basal and all-trans-retinal-stimulated ATPase activities were reduced substantially for P and PV but only mildly for V. Electron microscopy revealed marked structural changes and misfolding for the P and PV mutants but few changes for the V mutant, consistent with the disease severity difference in patients. We generated Abca4(PV/PV) knock-in mice homozygous for the complex PV allele to investigate the effects of this misfolding mutation in vivo. Mutant ABCA4 RNA levels approximated WT ABCA4 RNA levels but, surprisingly, only trace amounts of mutant ABCA4 protein were noted in the retina. RNA sequencing of WT, Abca4(-/-) and Abca4(PV/PV) mice revealed mild gene expression alterations in the retina and RPE. Similar to Abca4(-/-) mice, Abca4(PV/PV) mice showed substantial A2E and lipofuscin accumulation in their RPE cells but no retinal degeneration up to 12 months of age. Thus, rapid degradation of this large misfolded mutant protein in mouse retina caused little detectable photoreceptor degeneration. These findings suggest likely differences in the unfolded protein response between murine and human photoreceptors and support development of therapies directed at increasing this capability in patients.

Gene Expression

Genetic Association Studies

Retinal Degeneration - genetics

Humans

Mice, Inbred C57BL

Cercopithecus aethiops

Mice, 129 Strain

Disease Progression

Protein Folding

Mice, Knockout

Protein Transport

Point Mutation

Animals

ATP-Binding Cassette Transporters - genetics

Age of Onset

HEK293 Cells

ATP-Binding Cassette Transporters - metabolism

Adult

Retinal Degeneration - pathology

COS Cells

Retinal Degeneration - enzymology

Details

Title: Subtitle: Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations
Creators: Ning Zhang - Department of Pharmacology and Cleveland Center for Membrane and Structural Biology and
Yaroslav Tsybovsky - Department of Pharmacology and Cleveland Center for Membrane and Structural Biology and
Alexander V Kolesnikov - Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8096, Saint Louis, MO 63110, USA
Malgorzata Rozanowska - Department of Ophthalmology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Malgorzata Swider - Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Sharon B Schwartz - Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Edwin M Stone - Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, IA, USA Howard Hughes Medical Institute, Iowa City, IA, USA and
Grazyna Palczewska - Polgenix, Inc., 11000 Cedar Ave, Suite 260, Cleveland, OH 44106, USA
Akiko Maeda - Department of Ophthalmology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Vladimir J Kefalov - Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8096, Saint Louis, MO 63110, USA
Samuel G Jacobson - Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Artur V Cideciyan - Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Krzysztof Palczewski - Department of Pharmacology and Cleveland Center for Membrane and Structural Biology and kxp65@case.edu
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.24(11), pp.3220-3237
DOI: 10.1093/hmg/ddv073
PMID: 25712131
PMCID: PMC4424957
NLM abbreviation: Hum Mol Genet
ISSN: 1460-2083
eISSN: 1460-2083
Publisher: England
Grant note: P30 EY011373 / NEI NIH HHS EY021126 / NEI NIH HHS EY13203 / NEI NIH HHS R01 EY019312 / NEI NIH HHS AG043645 / NIA NIH HHS K08EY019031 / NEI NIH HHS EY009339 / NEI NIH HHS EY019312 / NEI NIH HHS P30 EY11373 / NEI NIH HHS EY022658 / NEI NIH HHS
Language: English
Date published: 06/01/2015
Academic Unit: Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983979951002771

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