The Retromer Complex Is Required for Rhodopsin Recycling and Its Loss Leads to Photoreceptor Degeneration

Abstract

Rhodopsin recycling via the retromer, rather than degradation through lysosomes, can alleviate light-induced photoreceptor degeneration in Drosophila.

VPS26A–SNX27 Interaction-Dependent mGluR5 Recycling in Dorsal Horn Neurons Mediates Neuropathic Pain in Rats

“…In, input control; IP, immunoprecipitation. VPS26A-bound VPS26A, one-way ANOVA, F (6,35) ϭ 11.54, p Ͻ 0.001; VPS26A-bound SNX27, one-way ANOVA, F (6,35) ϭ 11.42, p Ͻ 0.001; VPS26A-bound mGluR5, one-way ANOVA, F (6,35) ϭ 8.778, p Ͻ 0.001; mGluR5-bound mGluR5, one-way ANOVA, F (6,35) ϭ 13.39, p Ͻ 0.001; mGluR5-bound VPS26A, one-way ANOVA, F (6,35) photoreceptor protein recycling; conversely, the lack of retromer resulted in the improper recycling and the degeneration of photoreceptor protein (Wang et al, 2014). Together, these data reveal that the SNL-enhanced VPS26A-SNX27 interaction is necessary and sufficient to regulate the endosomal recycling of mGluR5, which possibly impedes lysosomal degradation and promotes the membrane insertion of mGluR5 underlying the development of neuropathic pain.…”

The retromer complex in development and disease

“…For example, unlike the loss of wls and wg, the loss of Vps26 or Vps35 does not cause oversized eyes (Bartscherer et al, 2006;Wang et al, 2014), suggesting that Wg signaling during eye development is not dependent on Vps35 or Vps26. In addition, the retromer complex seems to be dispensable for the transduction or fine-tuning of other signaling pathways that are known to be regulated by vesicular trafficking.…”

“…In addition, the retromer complex seems to be dispensable for the transduction or fine-tuning of other signaling pathways that are known to be regulated by vesicular trafficking. Indeed, no phenotypes consistent with defects in the Hedgehog, Notch or BMP pathways during wing development have been observed following the knockdown of retromer components (Belenkaya et al, 2008;Franch-Marro et al, 2008;Port et al, 2008;Wang et al, 2014), suggesting that retromer-dependent trafficking in general does not play a crucial regulatory role in all developmental signaling pathways.…”

“…Much of the endocytosed rhodopsin is degraded in lysosomes. However, recent studies indicate that a significant portion of internalized rhodopsin can be recycled via the retromer complex (Wang et al, 2014). In the absence of Vps26 or Vps35, rhodopsin aberrantly accumulates in endosomes and overwhelms the endolysosomal system, and it also forms a toxic complex with Arrestin 2 (Alloway et al, 2000), giving rise to the severe photoreceptor degeneration observed in retromer mutants upon light exposure (Wang et al, 2014).…”

“…Retromer function has therefore been implicated in various developmental contexts, including wing development in Drosophila (Belenkaya et al, 2008;Franch-Marro et al, 2008;Port et al, 2008), epithelial tissue polarity (de Vreede et al, 2014;Pocha et al, 2011;Zhou et al, 2011) and heme formation . In addition, the retromer complex is essential for the maintenance of neurons (Wang et al, 2014), and impaired retromer function has been implicated in human neurodegenerative diseases, including Alzheimer's disease (Muhammad et al, 2008;Small et al, 2005;Wen et al, 2011) and Parkinson's disease (Vilariño-Güell et al, 2011;Zimprich et al, 2011). In this article, we summarize how the retromer complex functions and interacts with other molecules to mediate protein endocytic recycling.…”