May 2005
Volume 46, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2005
Opa1 Loss and Retinal Ganglion Cell Death
Author Affiliations & Notes
  • W.–K. Ju
    Center for Neuroscience and Aging,
    The Burnham Institute, La Jolla, CA
  • Y. Kushnareva
    Center for Neuroscience and Aging,
    The Burnham Institute, La Jolla, CA
  • B. Bossy
    Center for Neuroscience and Aging,
    The Burnham Institute, La Jolla, CA
  • R. Schwarzenbacher
    Center for Infectious Disease,
    The Burnham Institute, La Jolla, CA
  • R. Liddington
    Center for Infectious Disease,
    The Burnham Institute, La Jolla, CA
  • A. White
    Neurosciences, National Center for Microscopy and Imaging Research, University of California, San Diego, CA
  • M. Ellisman
    Neurosciences, National Center for Microscopy and Imaging Research, University of California, San Diego, CA
  • G. Perkins
    Neurosciences, National Center for Microscopy and Imaging Research, University of California, San Diego, CA
  • S. Lipton
    Center for Neuroscience and Aging,
    The Burnham Institute, La Jolla, CA
  • E. Bossy–Wetzel
    Center for Neuroscience and Aging,
    The Burnham Institute, La Jolla, CA
  • Footnotes
    Commercial Relationships  W. Ju, None; Y. Kushnareva, None; B. Bossy, None; R. Schwarzenbacher, None; R. Liddington, None; A. White, None; M. Ellisman, None; G. Perkins, None; S. Lipton, None; E. Bossy–Wetzel, None.
  • Footnotes
    Support  NIH grant RO1 NS047456, RO1 NS04431, PO1 HD29587, RO1 NS1418, RO1 EY05477, RO1 EY09024, RO1 NS41207
Investigative Ophthalmology & Visual Science May 2005, Vol.46, 5188. doi:
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      W.–K. Ju, Y. Kushnareva, B. Bossy, R. Schwarzenbacher, R. Liddington, A. White, M. Ellisman, G. Perkins, S. Lipton, E. Bossy–Wetzel; Opa1 Loss and Retinal Ganglion Cell Death . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5188.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: Dominant optic atrophy (DOA) is the most common form of hereditary optic neuropathy, leading to vision loss in young children. To date, DOA is an incurable neurodegenerative disorder characterized by loss of retinal ganglion cells. The gene defective in DOA is Optic Atrophy Type–1 (OPA1). Interestingly, OPA1 encodes a large dynamin–related GTPase localized to the mitochondrial inner membrane and implicated in mitochondrial fusion. A balance between mitochondrial fission (division) and fusion is critical for normal neuronal function. OPA1 mutation causes DOA characterized by retinal ganglion cell degeneration. However, mechanisms of retinal ganglion cell death are unknown. Methods: By using siRNA mediated gene silencing, the effects of OPA1 loss were analyzed with 3D time–lapse deconvolution microscopy and electron microscope tomography. For structural analyses of OPA1, we synthesized recombinant OPA protein and GTPase activity was measured at physiological salt concentration. For bioenergetic analyses, mitochondrial respiration and ATP level were measured. Results: Most missense mutations in OPA1 cluster in the conserved GTPase domain. Intriguingly, several missense mutations map directly to the active site for GTP binding and therefore are likely to either alter enzymatic activity or result in its loss. We show that recombinant OPA1 protein reveals GTPase activity, similar to Dynamin. Importantly, OPA1 knockdown by siRNA results in dramatic mitochondrial fission characterized by a conversion of tubular, fused mitochondria into isolated small organelles. Mitochondrial fission after OPA1 loss is accompanied by a decrease of ATP, respiratory inhibition, and ultrastructural abnormalities of mitochondria. Dominant–negative Drp–1 overexpression prevents mitochondrial fission following OPA1 loss. Conclusions: OPA1 loss of function may impair normal mitochondrial and neuronal function and lead to neurodegeneration.

Keywords: ganglion cells • retinal degenerations: hereditary • retinal degenerations: cell biology 
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