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.
Highlights
Retromer is essential for selective retrieval of transmembrane proteins from endosomes to trans-Golgi network [1,2,3]
VPS35 expression in developing mouse retinal ganglion cell (RGC), including melanopsin positive ipRGCs To investigate the potential role of VPS35 in retina, we first examined vps35’s expression in mouse retina by taking advantage of vps35+/m mice, in which LacZ gene is knocked in the intron of vps35 gene, the LacZ activity, under the control of vps35 promoter, can be used as a reporter for vps35’s expression [9,10,14]
The LacZ activity was detected in developing mouse retinas from embryonic 12.5 to all the ages examined (Figure 1A and data not shown). This LacZ activity was mainly distributed in the ganglion cell layer (GCL) of vps35+/m retinas (Figure 1A)
Summary
Retromer is essential for selective retrieval of transmembrane proteins from endosomes to trans-Golgi network [1,2,3]. Retromer contains two sub-protein complexes: the cargo-selective complex and membrane deformation complex [2,4]. VPS35 is the key component of the cargoselective complex, a trimer of VPS proteins VPS35, VPS29, and VPS26. Mutations in Vps gene is identified in patients of late-onset PD [5,6]. The retromer complex (e.g., Vps and Vps26) is decreased in the postmortem hippocampus of AD patients [7]. In Vps or Vps deficient animals, the major culprit of AD, β-amyloid (Aβ), is increased in the hippocampus [7,9].
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