April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Gamma-Synuclein Aggregation and Activation of Optic Nerve Head Astrocytes
Author Affiliations & Notes
  • N. Marsh-Armstrong
    Neuroscience and Ophthalmology,
    Johns Hopkins Univ Sch of Med, Baltimore, Maryland
  • I. Soto
    Neuroscience,
    Johns Hopkins Univ Sch of Med, Baltimore, Maryland
  • E. Oglesby
    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland
  • C.-H. O. Davis
    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland
  • E. H. Mules
    Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland
  • F. Valiente-Soriano
    Oftalmologia, Universidad de Murcia, Murcia, Spain
  • M. Vidal-Sanz
    Oftalmologia, Universidad de Murcia, Murcia, Spain
  • V. Buchman
    School of Biosciences, Cardiff University, Cardiff, United Kingdom
  • P. A. Watkins
    Neurology,
    Johns Hopkins Univ Sch of Med, Baltimore, Maryland
  • J. V. Nguyen
    Neuroscience,
    Johns Hopkins Univ Sch of Med, Baltimore, Maryland
  • Footnotes
    Commercial Relationships  N. Marsh-Armstrong, Author in U.S.P.T.0. Provisional Patent Application #61149892, P; I. Soto, Author in U.S.P.T.O. Provisional Patent Application #61149892, P; E. Oglesby, None; C.-H.O. Davis, None; E.H. Mules, None; F. Valiente-Soriano, None; M. Vidal-Sanz, None; V. Buchman, None; P.A. Watkins, None; J.V. Nguyen, None.
  • Footnotes
    Support  Glaucoma Research Foundation Catalyst For a Cure grant
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 2100. doi:
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      N. Marsh-Armstrong, I. Soto, E. Oglesby, C.-H. O. Davis, E. H. Mules, F. Valiente-Soriano, M. Vidal-Sanz, V. Buchman, P. A. Watkins, J. V. Nguyen; Gamma-Synuclein Aggregation and Activation of Optic Nerve Head Astrocytes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2100.

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

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Abstract

Purpose: : To evaluate whether there are gamma-synuclein aggregates in mouse glaucoma animal models, and to determine whether and how gamma-synuclein is protective or deleterious for retinal ganglion cells (RGC).

Methods: : Using antibodies, the presence of gamma-synuclein aggregates was examined by immunohistochemistry and Western blotting in DBA/2J mice. Levels of Mac-2 and Adipose Differentiation Related Protein (Adrp) proteins were analyzed in optic nerve head (ONH) longitudinal sections using novel segmentation-less image analyses. The number of RGC was determined in retina wholemounts by gamma-synuclein or neurofilament light mRNA expression. The number of RGC with somatic phosphorylated neurofilament (pNF+ RGC) was used to estimate the number of RGC with axonal injuries. Intraocular pressure (IOP) was elevated in C57BL/6J mice by translimbal laser photocoagulation.

Results: : We find gamma-synuclein aggregates in the retina of aged but not young DBA/2J by immunohistochemistry and Western blotting. The earliest formation of these aggregates occurs at the myelination transition zone (MTZ) of the ONH. There, a unique set of astrocytes expressing Mac-2 and other phagocytic genes enwrap large aggregates and dramatically upregulate Mac-2 and the lipid droplet marker Adrp in aged DBA/2J. In both RGC5 cells and MTZ astrocytes, the gamma-synuclein aggregates are associated with Adrp in lipid droplets. Both Mac-2 and Adrp are also upregulated in MTZ astrocytes one week after elevation of IOP in Sncg +/- mice. Sibling Sncg -/- mice upregulate Adrp but fail to upregulate Mac-2. The Sncg -/- mice also develop twice the number of pNF+ RGC.

Conclusions: : These studies demonstrate the presence of gamma-synuclein aggregates in two mouse models of glaucoma, indicating that glaucoma is a synucleinopathy similar to Parkinson’s disease. These studies also suggest that a previously unrecognized subpopulation of ONH astrocytes play a prominent phagocytic role in glaucoma. Further, they show that the gamma-synuclein aggregates are forms of the protein associated with lipid droplets, and that gamma-synuclein plays a protective function after acute axonal insult. These findings that are likely relevant not only to glaucoma but also to other synucleinopathies.

Keywords: astrocytes: optic nerve head • ganglion cells • apoptosis/cell death 
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