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

Wang, Shiuan; Tan, Kai Li; Agosto, Melina A.; Xiong, Bo; Yamamoto, Shinya; Sandoval, Héctor; Jaiswal, Manish; Bayat, Vafa; Zhang, Ke; Charng, Wu Lin; David, Gabriela; Duraine, Lita; Venkatachalam, Kartik; Wensel, Theodore G.; Bellen, Hugo J.

doi:10.1371/journal.pbio.1001847

Cited by 82 publications

(126 citation statements)

References 136 publications

(214 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Retromer, which crucially contributes to endosomal sorting machinery through the retrieval and recycling of signaling receptors away from degradation, has been identified as a critical element for glutamatergic-receptor-dependent neural plasticity at excitatory synapses. We observed it accompanied by behavioral allodynia; neuropathic injury time-dependently enhanced VPS26A and SNX27 expression; VPS26A-SNX27 coprecipitation; and VPS26A-positive, SNX27-positive, and VPS26A-SNX27 double-labeled immunoreactivity in the dorsal horn of Sprague Dawley rats that were all sufficiently ameliorated through the focal knock-down of spinal VPS26A expression. Although the knock-down of spinal SNX27 expression exhibited similar effects, spinal nerve ligation (SNL)-enhanced VPS26A expression remained unaffected. Moreover, SNL also increased membrane-bound and total mGluR5 abundance, VPS26A-bound SNX27 and mGluR5 and mGluR5-bound VPS26A and SNX27 coprecipitation, and mGluR5-positive and VPS26A/SNX27/mGluR5 triple-labeled immunoreactivity in the dorsal horn, and these effects were all attenuated through the focal knock-down of spinal VPS26A and SNX27 expression. Although administration with MPEP adequately ameliorated SNL-associated allodynia, mGluR5 expression, and membrane insertion, SNL-enhanced VPS26A and SNX27 expression were unaffected. Together, these results suggested a role of spinal VPS26A-SNX27-dependent mGluR5 recycling in the development of neuropathic pain. This is the first study that links retromer-associated sorting machinery with the spinal plasticity underlying pain hypersensitivity and proposes the possible pathophysiological relevance of endocytic recycling in pain pathophysiology through the modification of glutamatergic mGluR5 recycling.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…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.…”

Section: Retromer-mediated Control Of Wnt Signaling During Drosophilamentioning

confidence: 99%

“…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.…”

Section: Retromer-mediated Control Of Wnt Signaling During Drosophilamentioning

confidence: 99%

“…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).…”

Section: The Retromer Complex and The Maintenance Of Photoreceptorsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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The retromer complex in development and disease

Wang

Bellen

2015

Development

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The retromer complex is a multimeric protein complex involved in recycling proteins from endosomes to the trans-Golgi network or plasma membrane. It thus regulates the abundance and subcellular distribution of its cargo within cells. Studies using model organisms show that the retromer complex is involved in specific developmental processes. Moreover, a number of recent studies implicate aberrant retromer function in photoreceptor degeneration, Alzheimer's disease and Parkinson's disease. Here, and in the accompanying poster, we provide an overview of the molecular and cellular mechanisms of retromer-mediated protein trafficking, highlighting key examples of retromer function in vivo.

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Endosomal recycling and dopamine neurotransmission: Exploring the links between the retromer and Parkinson's disease

Gock

Follett

Rintoul

et al. 2022

Synapse

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The retromer complex is an evolutionarily conserved protein complex involved in the endosomal recycling of various cargo proteins. It is ubiquitously expressed in all tissue and is found in both invertebrate as well as mammalian nervous systems, where it recycles various synaptic membrane proteins including the dopamine transporter and dopamine D1 receptor, two proteins implicated in dopamine homeostasis and neurotransmission. The involvement of the retromer complex in dopamine neurobiology is further underscored by its links to Parkinson's disease, a neurodegenerative disorder of the dopamine system. In this article, the existing literature linking the retromer complex to synaptic function and dopamine homeostasis is reviewed. Additional possible links are highlighted by exploring the retromer and other Parkinson's disease‐associated proteins and possible relationships to synaptic function and dopamine transmission.

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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.

Cited by 82 publications

References 136 publications

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

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

The retromer complex in development and disease

Endosomal recycling and dopamine neurotransmission: Exploring the links between the retromer and Parkinson's disease

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