Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies.

Abstract

Mitochondrial optic neuropathies, that is, Leber hereditary optic neuropathy and dominant optic atrophy, selectively affect retinal ganglion cells, causing visual loss with relatively preserved pupillary light reflex. The mammalian eye contains a light detection system based on a subset of retinal ganglion cells containing the photopigment melanopsin. These cells give origin to the retinohypothalamic tract and support the non-image-forming visual functions of the eye, which include the photoentrainment of circadian rhythms, light-induced suppression of melatonin secretion and pupillary light reflex. We studied the integrity of the retinohypothalamic tract in five patients with Leber hereditary optic neuropathy, in four with dominant optic atrophy and in nine controls by testing the light-induced suppression of nocturnal melatonin secretion. This response was maintained in optic neuropathy subjects as in controls, indicating that the retinohypothalamic tract is sufficiently preserved to drive light information detected by melanopsin retinal ganglion cells. We then investigated the histology of post-mortem eyes from two patients with Leber hereditary optic neuropathy and one case with dominant optic atrophy, compared with three age-matched controls. On these retinas, melanopsin retinal ganglion cells were characterized by immunohistochemistry and their number and distribution evaluated by a new protocol. In control retinas, we show that melanopsin retinal ganglion cells are lost with age and are more represented in the parafoveal region. In patients, we demonstrate a relative sparing of these cells compared with the massive loss of total retinal ganglion cells, even in the most affected areas of the retina. Our results demonstrate that melanopsin retinal ganglion cells resist neurodegeneration due to mitochondrial dysfunction and maintain non-image-forming functions of the eye in these visually impaired patients. We also show that in normal human retinas, these cells are more concentrated around the fovea and are lost with ageing. The current results provide a plausible explanation for the preservation of pupillary light reaction despite profound visual loss in patients with mitochondrial optic neuropathy, revealing the robustness of melanopsin retinal ganglion cells to a metabolic insult and opening the question of mechanisms that might protect these cells.

DOI: 10.1093/brain/awq155

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@article{Morgia2010MelanopsinRG, title={Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies.}, author={Chiara la Morgia and Fred N. Ross-Cisneros and Alfredo Arrigo Sadun and Jens Hannibal and Alessandra Munarini and Vilma Mantovani and Piero Barboni and Gaetano Cantalupo and Kevin R. Tozer and Elisa Sancisi and Solange Rios Salom{\~a}o and Milton Nunes Moraes and Milton Nunes Moraes-Filho and Steffen Heegaard and Dan Milea and Poul Kjer and Pasquale Montagna and Valerio Carelli}, journal={Brain : a journal of neurology}, year={2010}, volume={133 Pt 8}, pages={2426-38} }