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.

Pathological Confirmation of Optic Neuropathy in Familial Dysautonomia

“…These abnormalities appear to worsen with age. Overall, these findings are similar to those described in mitochondrial optic neuropathies such as Leber hereditary optic neuropathy and dominant optic atrophy (16,17). …”

“…Pathological studies in Leber hereditary optic neuropathy and dominant optic atrophy have shown relatively preservation of melanopsin-containing ganglion cells in spite of extensive loss of the predominantly small midget/ parvocellular P-ganglion cells (17,24). This is because melanopsin retinal ganglion cells are more resistant to mitochondrial stress and neurodegeneration (17).…”

“…Pathological studies in Leber hereditary optic neuropathy and dominant optic atrophy have shown relatively preservation of melanopsin-containing ganglion cells in spite of extensive loss of the predominantly small midget/ parvocellular P-ganglion cells (17,24). This is because melanopsin retinal ganglion cells are more resistant to mitochondrial stress and neurodegeneration (17). The optic neuropathy observed in familial dysautonomia particularly resembles that seen in dominant optic atrophy, in which the optic nerve damage is present since childhood, even in visually asymptomatic patients, which can be proven by OCT (25).…”

Alzheimer’s disease: A review of its visual system neuropathology. Optical coherence tomography—a potential role as a study tool in vivo

“…Regarding sleep disturbances in AD, it is of note that recent studies documented impairment of melanopsin RGCs (m-RGCs) in the retina of patients with AD. m-RGCs are a population of RGCs (1-2 % of total RGC population) involved in non-image-forming visual functions, including photoentrainment of circadian rhythms [20]. In this study, m-RGC density was significantly decreased in the AD group compared with controls, and remaining mRGCs presented impaired function, altered morphology, and amyloid deposits in and around these cells.…”

Aging of human short-wave cone pathways

“…If the age-related losses in the S-cone IRF are attributable to changes in the ipRGCs themselves, reduced responsivity to melanopsin stimulation may also be expected in natural environments. Anatomical evidence indicates that there is a loss in ipRGCs in the elderly (39). Further study is warranted to assess possible contributions of these ganglion cells to disorders of sleep and dysfunction of circadian rhythms, which become more common with increasing age (40) and have decreased stimulation by short-wave light as the result of age-related changes in the ocular media (41).…”