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Vps35 haploinsufficiency results in degenerative-like deficit in mouse retinal ganglion neurons and impairment of optic nerve injury-induced gliosis.

Liu W, Tang FL, Erion J, Xiao H, Ye J, Xiong WC - Mol Brain (2014)

Bottom Line: VPS35 (vacuolar protein sorting 35) is a major component of retromer that selectively promotes endosome-to-Golgi retrieval of transmembrane proteins.RGCs from young adult Vps35 heterozygotes (Vps35+/m) show degenerative-like features, such as dystrophic dendrites, reduced axon fibers, and increased TUNEL labeled RGCs.Additionally, gliosis in the optic nerve is transiently elevated in neonatal, but reduced in aged Vps35+/m mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Ophthalmology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China. yejian1979@163.com.

ABSTRACT
VPS35 (vacuolar protein sorting 35) is a major component of retromer that selectively promotes endosome-to-Golgi retrieval of transmembrane proteins. Dysfunction of retromer is a risk factor for the pathogenesis of Parkinson's disease (PD) and Alzheimer's disease (AD), both neuro-degeneration disorders. However, VPS35/retromer's function in retina or the contribution of Vps35-deficiency to retinal neuro-degenerative disorders has not been investigated. Here we provide evidence for a role of VPS35 in mouse retinal ganglion cell (RGC) survival and regeneration. VPS35 is selectively expressed in developing mouse RGCs. RGCs from young adult Vps35 heterozygotes (Vps35+/m) show degenerative-like features, such as dystrophic dendrites, reduced axon fibers, and increased TUNEL labeled RGCs. Additionally, gliosis in the optic nerve is transiently elevated in neonatal, but reduced in aged Vps35+/m mice. Optic nerve injury-induced gliosis is also attenuated in Vps35+/m mice. These results suggest that Vps35 is necessary for mouse RGC survival and regeneration, and Vps35-deficiency may contribute to the pathogenesis of retinal ganglion neuro-degeneration, a critical pathology leading to the blindness of many retinal degenerative disorders.

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Reduced RGC axon fibers in P30 vps35+/m retinas. (A-B) Immunostaining analysis using anti-neurofilament antibodies of flat-mounted retinas (A) and cross sections (B) from P30 Vps35+/+ and +/m mice. In A, the bottom two panels are amplified images from the marked squares in upper panel. OD: optic disc; NF: nerve fiber. (C) Immunostaining analysis using anti-Tuj1antibodies of flat-mounted retinas from P30 Vps35+/+ and +/m mice. Scale bars in A-C, 50 μm. (D) Quantification analysis of the ratio of nerve fibers verse RGC somas stained by anti-Tuj1. (E) Quantification analysis of RGC soma density. In (D-E), mean +/- SEM (n = 5 retinas) were shown. *, P < 0.05.
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Figure 3: Reduced RGC axon fibers in P30 vps35+/m retinas. (A-B) Immunostaining analysis using anti-neurofilament antibodies of flat-mounted retinas (A) and cross sections (B) from P30 Vps35+/+ and +/m mice. In A, the bottom two panels are amplified images from the marked squares in upper panel. OD: optic disc; NF: nerve fiber. (C) Immunostaining analysis using anti-Tuj1antibodies of flat-mounted retinas from P30 Vps35+/+ and +/m mice. Scale bars in A-C, 50 μm. (D) Quantification analysis of the ratio of nerve fibers verse RGC somas stained by anti-Tuj1. (E) Quantification analysis of RGC soma density. In (D-E), mean +/- SEM (n = 5 retinas) were shown. *, P < 0.05.

Mentions: We then examined RGCs in both flat-mounted and cross-sectioned retina derived from P30 vps35+/+ and +/m mice by immunostaining analysis of neurofilament. Whereas the numbers and distribution of RGC somas appeared to be normal in vps35+/m retina, RGC nerve fibers labeled by neurofilament were reduced in vps35+/m retinas as compared to that in vps35+/+ controls (Figures 3A-E), implicating axonal deficit of RGCs in vps35 mutant retina. Being consistent, immunostaining analysis using anti-Tuj1 antibody also showed reduced Tuj1+ RGC axons, but not somas, in the mutant retinas (Figures 3C-E). These alterations in vps35+/- retina resembled to that of dystrophic RGC axons.


Vps35 haploinsufficiency results in degenerative-like deficit in mouse retinal ganglion neurons and impairment of optic nerve injury-induced gliosis.

Liu W, Tang FL, Erion J, Xiao H, Ye J, Xiong WC - Mol Brain (2014)

Reduced RGC axon fibers in P30 vps35+/m retinas. (A-B) Immunostaining analysis using anti-neurofilament antibodies of flat-mounted retinas (A) and cross sections (B) from P30 Vps35+/+ and +/m mice. In A, the bottom two panels are amplified images from the marked squares in upper panel. OD: optic disc; NF: nerve fiber. (C) Immunostaining analysis using anti-Tuj1antibodies of flat-mounted retinas from P30 Vps35+/+ and +/m mice. Scale bars in A-C, 50 μm. (D) Quantification analysis of the ratio of nerve fibers verse RGC somas stained by anti-Tuj1. (E) Quantification analysis of RGC soma density. In (D-E), mean +/- SEM (n = 5 retinas) were shown. *, P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4016418&req=5

Figure 3: Reduced RGC axon fibers in P30 vps35+/m retinas. (A-B) Immunostaining analysis using anti-neurofilament antibodies of flat-mounted retinas (A) and cross sections (B) from P30 Vps35+/+ and +/m mice. In A, the bottom two panels are amplified images from the marked squares in upper panel. OD: optic disc; NF: nerve fiber. (C) Immunostaining analysis using anti-Tuj1antibodies of flat-mounted retinas from P30 Vps35+/+ and +/m mice. Scale bars in A-C, 50 μm. (D) Quantification analysis of the ratio of nerve fibers verse RGC somas stained by anti-Tuj1. (E) Quantification analysis of RGC soma density. In (D-E), mean +/- SEM (n = 5 retinas) were shown. *, P < 0.05.
Mentions: We then examined RGCs in both flat-mounted and cross-sectioned retina derived from P30 vps35+/+ and +/m mice by immunostaining analysis of neurofilament. Whereas the numbers and distribution of RGC somas appeared to be normal in vps35+/m retina, RGC nerve fibers labeled by neurofilament were reduced in vps35+/m retinas as compared to that in vps35+/+ controls (Figures 3A-E), implicating axonal deficit of RGCs in vps35 mutant retina. Being consistent, immunostaining analysis using anti-Tuj1 antibody also showed reduced Tuj1+ RGC axons, but not somas, in the mutant retinas (Figures 3C-E). These alterations in vps35+/- retina resembled to that of dystrophic RGC axons.

Bottom Line: VPS35 (vacuolar protein sorting 35) is a major component of retromer that selectively promotes endosome-to-Golgi retrieval of transmembrane proteins.RGCs from young adult Vps35 heterozygotes (Vps35+/m) show degenerative-like features, such as dystrophic dendrites, reduced axon fibers, and increased TUNEL labeled RGCs.Additionally, gliosis in the optic nerve is transiently elevated in neonatal, but reduced in aged Vps35+/m mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Ophthalmology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China. yejian1979@163.com.

ABSTRACT
VPS35 (vacuolar protein sorting 35) is a major component of retromer that selectively promotes endosome-to-Golgi retrieval of transmembrane proteins. Dysfunction of retromer is a risk factor for the pathogenesis of Parkinson's disease (PD) and Alzheimer's disease (AD), both neuro-degeneration disorders. However, VPS35/retromer's function in retina or the contribution of Vps35-deficiency to retinal neuro-degenerative disorders has not been investigated. Here we provide evidence for a role of VPS35 in mouse retinal ganglion cell (RGC) survival and regeneration. VPS35 is selectively expressed in developing mouse RGCs. RGCs from young adult Vps35 heterozygotes (Vps35+/m) show degenerative-like features, such as dystrophic dendrites, reduced axon fibers, and increased TUNEL labeled RGCs. Additionally, gliosis in the optic nerve is transiently elevated in neonatal, but reduced in aged Vps35+/m mice. Optic nerve injury-induced gliosis is also attenuated in Vps35+/m mice. These results suggest that Vps35 is necessary for mouse RGC survival and regeneration, and Vps35-deficiency may contribute to the pathogenesis of retinal ganglion neuro-degeneration, a critical pathology leading to the blindness of many retinal degenerative disorders.

Show MeSH
Related in: MedlinePlus