title: 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.
authors.affiliation: Department of Neurological Sciences, University of Bologna, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.forename: Fred N
authors.initials: FN
authors.lastname: Ross-Cisneros
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Sadun
authors.forename: Jens
authors.initials: J
authors.lastname: Hannibal
authors.forename: Alessandra
authors.initials: A
authors.lastname: Munarini
authors.forename: Vilma
authors.initials: V
authors.lastname: Mantovani
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.forename: Gaetano
authors.initials: G
authors.lastname: Cantalupo
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Tozer
authors.forename: Elisa
authors.initials: E
authors.lastname: Sancisi
authors.forename: Solange R
authors.initials: SR
authors.lastname: Salomao
authors.forename: Milton N
authors.initials: MN
authors.lastname: Moraes
authors.forename: Milton N
authors.initials: MN
authors.lastname: Moraes-Filho
authors.forename: Steffen
authors.initials: S
authors.lastname: Heegaard
authors.forename: Dan
authors.initials: D
authors.lastname: Milea
authors.forename: Poul
authors.initials: P
authors.lastname: Kjer
authors.forename: Pasquale
authors.initials: P
authors.lastname: Montagna
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology / Q000502:physiology; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D029241:Optic Atrophy, Autosomal Dominant / Q000473:pathology / Q000503:physiopathology*; D029242:Optic Atrophy, Hereditary, Leber / Q000473:pathology / Q000503:physiopathology*; D012160:Retina / Q000473:pathology / Q000503:physiopathology; D012165:Retinal Ganglion Cells / Q000473:pathology / Q000502:physiology*; D017299:Rod Opsins / Q000378:metabolism*; D014795:Visual Pathways / Q000473:pathology / Q000503:physiopathology*; D000099210:Melanopsin
chemical_list: D017299:Rod Opsins; D000099210:Melanopsin