Retinal ganglion cell loss in kinesin-1 cargo Alcadein α deficient mice

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 Alcαdeficient 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/mm 2 vs. 208 ± 28.4 cells/mm 2 , 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. Alcαdeficient 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.

Retinal cadherins and the retinal cadherinopathies: Current concepts and future directions

“…All three are expressed in the developing retina with strongest and most sustained expression in the RGCs (de Ramon Francas et al, 2017). Cstn1 (also called Alc) mouse mutants underwent progressive RGC death beginning at 3 months of age: Other retinal layers were unaffected, and intraocular pressure was not elevated (Nakano et al, 2020). The mechanism for this cell death is unknown, but calsyntenins act as linkers between kinesin 1 motor proteins and vesicular cargo in microtubule transport (Konecna et al, 2006), suggesting that deficiencies in transport along the ganglion cell axon could be the underlying cause.…”

Age-related visual impairments and retinal ganglion cells axonal degeneration in a mouse model harboring OPTN (E50K) mutation

“…Dysfunction of axonal transport is a significant pathological event leading to many adult neurodegenerative diseases (AONDs) [ 24 ]. In another study, deficiency of cargo adaptors in axon led to age-related RGCs loss [ 25 ]. These indicated the significant role of axonal dysfunction in RGCs degradation, and also prompted us to investigate the retrograde and anterograde axonal transport in E50K mice of different ages.…”

“…As for the above series of assessment of RGCs axonal transport, CTB binds to ganglioside-monosialic acid-1 (GM1) on the surface of nerve cells like RGCs, and then was transported from cell soma to synapse via axonal transport, or the reverse route [ 25 ], indicating that tracing neurons axons through CTB-conjugated fluorescence is an effective way to assess axonal transport although this approach could be indirect when used alone. Namely when axon terminal activity gets lower, CTB uptake may be impeded, thus affecting transport evaluation.…”