Mistargeting of secretory cargo in retromer-deficient cells

Neuman, Sarah D.; Terry, Erica L.; Selegue, Jane E.; Cavanagh, Amy T.; Bashirullah, Arash

doi:10.1101/2020.07.02.185660

Cited by 5 publications

(6 citation statements)

References 61 publications

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“…2). The reduction in pRab12/Rab12 may reflect a compensatory increase in endo-lysosomal flux as retromer cargos are inadvertently retained, rather than efficiently recycled [48][49][50] . Hence, in agreement with others, we provide in-vivo evidence that Vps35 p.D620N results in a gain-of-function with respect to LRRK2 kinase activity 23 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine dynamics in VPS35 p.D620N knock-in mice

Follett

Tatarnikov

et al. 2023

Preprint

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Dysregulation of dopamine neurotransmission profoundly affects motor, motivation and learning behaviors, and is often observed during the prodromal phase of Parkinson's disease (PD). However, the mechanism underlying these pathophysiological changes remains to be elucidated. Mutations in vacuolar protein sorting 35 (VPS35) and leucine-rich repeat kinase 2 (LRRK2) both lead to autosomal dominant PD, and VPS35 and LRRK2 may physically interact to govern the trafficking of synaptic cargos within the endo-lysosomal network in a kinase-dependent manner. To better understand the functional role of VPS35 and LRRK2 on dopamine physiology, we examined Vps35 haploinsufficient (Haplo) and Vps35 p.D620N knock-in (VKI) mice and how their behavior, dopamine kinetics and biochemistry are influenced by LRRK2 kinase inhibitors. We found Vps35 p.D620N significantly elevates LRRK2-mediated phosphorylation of Rab10, Rab12 and Rab29. In contrast, Vps35 haploinsufficiency reduces phosphorylation of Rab12. While striatal dopamine transporter (DAT) expression and function is similarly impaired in both VKI and Haplo mice, that physiology is normalized in VKI by treatment with the LRRK2 kinase inhibitor, MLi-2. As a corollary, VKI animals show a significant increase in amphetamine induced hyperlocomotion, compared to Haplo mice, that is also abolished by MLi-2. Taken together, these data show Vps35 p.D620N confers a gain-of-function with respect to LRRK2 kinase activation, and VPS35 and LRRK2 functionally interact to regulate DAT trafficking and striatal dopamine neurotransmission.

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Section: Discussionmentioning

confidence: 99%

Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine dynamics in VPS35 p.D620N knock-in mice

Follett

Tatarnikov

et al. 2023

Preprint

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“…Endocytic recycling contributes to membrane receptor abundance, cell resensitization, and downstream signaling (Sannerud et al, 2003;Lucas and Hierro, 2017). Protein recycling is also important in the regulated secretion of hormones and neuropeptides (Ferraro et al, 2005;Chen et al, 2020;Neuman et al, 2021).…”

Section: Endocytic Recycling Of Proteins In the Regulated Secretory P...mentioning

confidence: 99%

“…Retromer is an evolutionarily conserved complex that regulates the retrograde pathway across all eukaryotes (Koumandou et al, 2011;McGough and Cullen, 2011;Chamberland and Ritter, 2017). In Saccharomyces cerevisiae, where retromer was first discovered, five vacuolar protein sorting (VPS) proteins compose the two retromer subcomplexes: the cargo-selective complex and the tubulation complex, both of which are conserved in higher eukaryotes (Seaman et al, 1998;Neuman et al, 2021). The cargo-selective complex is a trimer of Vps26, Vps29, and Vps35, which recruits cargo via an association between Vps35 and a sorting motif located within the cytoplasmic tail of cargo (Seaman et al, 1998).…”

Section: Retromer Evolution and Functionmentioning

confidence: 99%

Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion

Štepihar,

Florke Gee,

Hoyos Sanchez

et al. 2023

Front. Cell Dev. Biol.

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Intracellular protein trafficking and sorting are extremely arduous in endocrine and neuroendocrine cells, which synthesize and secrete on-demand substantial quantities of proteins. To ensure that neuroendocrine secretion operates correctly, each step in the secretion pathways is tightly regulated and coordinated both spatially and temporally. At the trans-Golgi network (TGN), intrinsic structural features of proteins and several sorting mechanisms and distinct signals direct newly synthesized proteins into proper membrane vesicles that enter either constitutive or regulated secretion pathways. Furthermore, this anterograde transport is counterbalanced by retrograde transport, which not only maintains membrane homeostasis but also recycles various proteins that function in the sorting of secretory cargo, formation of transport intermediates, or retrieval of resident proteins of secretory organelles. The retromer complex recycles proteins from the endocytic pathway back to the plasma membrane or TGN and was recently identified as a critical player in regulated secretion in the hypothalamus. Furthermore, melanoma antigen protein L2 (MAGEL2) was discovered to act as a tissue-specific regulator of the retromer-dependent endosomal protein recycling pathway and, by doing so, ensures proper secretory granule formation and maturation. MAGEL2 is a mammalian-specific and maternally imprinted gene implicated in Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. In this review, we will briefly discuss the current understanding of the regulated secretion pathway, encompassing anterograde and retrograde traffic. Although our understanding of the retrograde trafficking and sorting in regulated secretion is not yet complete, we will review recent insights into the molecular role of MAGEL2 in hypothalamic neuroendocrine secretion and how its dysregulation contributes to the symptoms of Prader-Willi and Schaaf-Yang patients. Given that the activation of many secreted proteins occurs after they enter secretory granules, modulation of the sorting efficiency in a tissue-specific manner may represent an evolutionary adaptation to environmental cues.

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“…Animals were synchronized at the onset of mucin/glue biogenesis as previously described (Neuman et al, 2021). Given that there is some degree of variability in developmental rates between animals, a second layer of tissue-autonomous synchronization was used to further confirm developmental stages.…”

Section: Developmental Stagingmentioning

confidence: 99%

A novel function for Rab proteins during maturation of secretory granules

et al. 2021

Preprint

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Regulated exocytosis is an essential process whereby professional secretory cells synthesize and secrete specific cargo proteins in a stimulus-dependent manner. Cargo-containing secretory granules are synthesized in the trans-Golgi Network (TGN); after budding from the TGN, granules undergo many modifications, including a dramatic increase in size. These changes occur during a poorly understood process called secretory granule maturation. Here we leverage the professional secretory cells of the Drosophila larval salivary glands as a model system to characterize a novel and unexpected role for Rab GTPases during secretory granule maturation. We find that secretory granules in the larval salivary glands increase in size ~300-fold between biogenesis and release, and loss of Rab1 or Rab11 dramatically reduces granule size. Surprisingly, we find that Rab1 and Rab11 protein localize to secretory granule membranes. Rab11 associates with granule membranes throughout the maturation process, and Rab11 is required for recruitment of Rab1. In turn, Rab1 associates specifically with immature secretory granules and drives granule growth. In addition to their roles in granule growth, both Rab1 and Rab11 appear to have additional roles during exocytosis; Rab11 function is necessary for exocytosis, while the presence of Rab1 on immature granules may prevent precocious exocytosis. Overall, these results highlight a new and unexpected role for Rab GTPases in secretory granule maturation.

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Mistargeting of secretory cargo in retromer-deficient cells

Cited by 5 publications

References 61 publications

Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine dynamics in VPS35 p.D620N knock-in mice

Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine dynamics in VPS35 p.D620N knock-in mice

Cell-specific secretory granule sorting mechanisms: the role of MAGEL2 and retromer in hypothalamic regulated secretion

A novel function for Rab proteins during maturation of secretory granules

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