Rhesus macaques with an <i>OPA1</i> mutation demonstrate features of autosomal dominant optic atrophy
Abstract
Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy primarily caused by mutations in OPA1 . We identified and defined a spontaneous nonhuman primate (NHP) model of ADOA using rhesus macaques heterozygous for a missense mutation ( OPA1 A8S). With ocular examinations, ophthalmic imaging, electroretinography, histopathology, immunohistochemistry, and transmission electron microscopy (TEM), we documented retinal nerve fiber layer (RNFL) thinning, retinal ganglion cell (RGC) loss and dysfunction, OPA1 mislocalization, and reduced axonal mitochondrial density in affected macaques. Our investigation revealed substantial phenotypic variability among affected macaques, shedding light on the pathogenesis of ADOA. The retinas were evaluated using techniques such as spectral-domain optical coherence tomography and fundus photography facilitating observation of structural changes in the retina and optic nerve. Thinning of the RNFL and optic nerve head degeneration, hallmark features of ADOA, were observed in affected macaques. Decreased RGC function in the OPA1 heterozygotes was demonstrated with pattern electroretinography. Histopathological analysis and immunohistochemical staining of postmortem retinal tissue suggested RGC loss in the papillomacular bundle, with reduced OPA1 and mitochondria in the RGC axons, indicating dysfunctional mitochondrial dynamics and reduced function consistent with ADOA. Ultrastructural changes were evident with TEM including dysmorphic mitochondria, axonal loss, myelin disruption, and hypertrophic astrocytic processes. The observed similar pattern of RGC loss and dysfunction coupled with phenotypic heterogeneity in our NHP model reflects the clinical variability observed in human ADOA patients indicating that therapeutic interventions in this foveate model will likely translate to the human condition.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (28)
Tracy N. Jaggers
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Ana Ripolles-Garcia
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Ala Moshiri
Department of Ophthalmology & Vision Science
Brett D. Story
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Jun Wang
Rui Chen
Lucy G. Moore
Department of Ophthalmology and Vision Science, School of Medicine, University of California, Davis
Leandro B. C. Teixeira
Comparative Ocular Pathology Laboratory of Wisconsin, School of Veterinary Medicine, University of Wisconsin-Madison
Jaeho Shim
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Ana C. Raposo
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Maria Isabel Casanova
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Sophie M. Le
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Sangwan Park
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Laura J. Young
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Soohyun Kim
Department of Biochemistry, Stanford University School of Medicine
Karolina P. Roszak
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Vanessa Ureno
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Paige M. Karpinen
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Nayeli Echeverria
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Monica Ardon
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Brian C. Leonard
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Marguerite Knipe
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis
Eliza Bliss-Moreau
Department of Psychology, California National Primate Research Center, University of California, Davis
Brad Fortune
Legacy Devers Eye Institute
J. Timothy Stout
Cullen Eye Institute, Baylor College of Medicine
Jeffrey Rogers
Nicholas Marsh-Armstrong
Department of Ophthalmology and Vision Science, School of Medicine, University of California, Davis
Sara M. Thomasy
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis