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F. N. Ross-Cisneros, C. La Morgia, J. Hannibal, M. N. Moraes, M. N. Moraes-Filho, V. Carelli, A. A. Sadun; Melanopsin-Containing Retinal Ganglion Cells are Partially Spared by Neurodegeneration in Leber’s Hereditary Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2559.
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To verify if intrinsically photosensitive melanopsin-containing retinal ganglion cells (ipRGCs) are involved in Leber’s hereditary optic neuropathy (LHON), which selectively affect retinal ganglion cells (RGCs). The non-rod/cone photoreceptors ipRGCs convey the detection of light irradiance to the brain through the retino-hypothalamic tract, photoentraining circadian rhythms and contributing to the pupillary light reflex (PLR).
Eyes from two LHON patients and two age-matched controls were collected at autopsy for histological and immunohistochemical investigations. Both patients carried the homoplasmic 11778/ND4 mutation and were affected by a mild and severe form of optic atrophy, respectively. Anti-human melanopsin antibodies were used to identify and count ipRGCs on 5µm thick retinal sections (1 every 5 serial sections) taken sagittally through the optic nerve head with temporal-nasal orientation. The total retinal surface of the 5 sections was calculated and density of ipRGCs determined. ipRGCs count was performed separately for the temporal and nasal sides of the retina, considering the optic nerve head as reference point. The number of residual axons was evaluated for the LHON eyes on post-laminar optic nerve cross-sections stained with p-phenylenediamine.
Immunohistochemical analysis of the retinas revealed a relative sparing of ipRGCs in LHON compared to controls despite the severe loss of RGCs (75% and 98% respectively). In control retinas the mean ipRGCs/RGCs (1.200.000 as average in humans) percentage was 1.4%. In the LHON eyes, for which we manually counted spared axons, the mean ipRGCs/RGCs (residual) percentage was 3.3% and 31.3%, respectively in the mild and severe LHON patients. Considering separately the ipRGCs count for the temporal vs nasal hemiretinas, we found a slightly higher amount of ipRGCs on the temporal side, despite this is the site of maximal degeneration in LHON.
This study demonstrates a substantial sparing of ipRGCs, in LHON despite the extensive loss of total RGCs due to the neurodegenerative process. This surprising finding explains why in LHON patients the PLR is usually maintained and suggests that circadian photoentrainment is preserved. It remains to be elucidated as to how ipRGCs are selectively spared by neurodegeneration.
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