Abstract
Maintenance of retinal ganglion cells (RGCs) activity is relied on axonal transport conveying materials required for their survival such as neurotrophic factors. Kinesin-1 undergoes anterograde transport in axons, and Alcadein α (Alcα; also called calsyntenin-1) is a major cargo adaptor protein that can drive kinesin-1 to transport vesicles containing Alcα. The long-term effects of Alcα-deficiency on retinal morphology and survival of RGCs during postnatal development were examined in Alcα knockout mice. At 1.5, 3, 6, and 15 months postnatal, the number of retrogradely labeled RGCs was determined in flat-mounted retinas of Alcα-deficient and wild-type mice. Retinal damage was assessed histologically by determining the retinal thickness. Intraocular pressure (IOP) was measured with a Tonolab tonometer. At 1.5 months postnatal, the number of retrogradely labeled RGCs was not different between wild-type and Alcα-deficient mice. However, at 3, 6, and 15 months postnatal, the number of RGCs was significantly lower in Alcα deficient mice than those of wild-type mice (143 ± 41.1 cells/mm2 vs. 208 ± 28.4 cells/mm2, respectively, at 3 months; P < 0.01). No differences were seen in retinal thickness or IOP between the two types of mice at any postnatal age. Alcα-deficient mice showed spontaneous loss of RGCs but no elevation in IOP. These mice mimic normal-tension glaucoma and will be useful for investigating the mechanism of neurodegeneration in this disorder and for developing treatments for RGC loss that does not involve changes in IOP.
Highlights
Glaucoma involves axon pathology of retinal ganglion cells (RGCs) and is more commonly seen in older people and those with elevated intraocular pressure (IOP)[1]
Alcadein α (Alcα) is expressed in retina including RGCs, which is not detected in Alcα knockout mice, confirming their Alcα-deficiency in the retina (Fig. 1)
We examined if there is difference in RGCs between 15-month-old wild-type and Alcα-deficient mice by retrogradely labelling RGCs with Fast Blue bilaterally injected into their superior colliculi
Summary
Glaucoma involves axon pathology of retinal ganglion cells (RGCs) and is more commonly seen in older people and those with elevated intraocular pressure (IOP)[1]. Multiple stimuli induce neuronal apoptosis, which may be reversed by neurotrophic factors that promote neuronal development and survival[2]. RGC survival is mediated by brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF)[3]. Intact axonal transport is prerequisite for transducing such trophic signals, and impaired axonal transport is recognized as an initial pathological event commonly observed in neurodegenerative disorders[4]. Deficits in axonal transport were observed after elevation of IOP5, it is still unclear whether attenuation of axonal transport could be a cause for RGC degeneration
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