Expression of sorting nexin 12 is regulated in developing cerebral cortical neurons

Mizutani, Reiko; Nakamura, Kazuaki; Kato, Natsuko; Aizawa, Kazuko; Miyamoto, Yuki; Torii, Tomohiro; Yamauchi, Junji; Tanoue, Akito

doi:10.1002/jnr.22795

Cited by 10 publications

(13 citation statements)

References 25 publications

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“…Recently one study reported that SNX12 is widely expressed in the adult mouse central nervous system and thus suggested that SNX12 might regulate neurite formation during cerebral cortical development [26]. Herein, we found that SNX12 is abundantly expressed in mouse cerebrum and cerebellum in addition to other tissues (Figure 2A).…”

Section: Resultsmentioning

confidence: 50%

Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing

Zhao

Wang

Yang

et al. 2012

Mol Neurodegeneration

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Backgroundβ-site APP cleaving enzyme 1 (BACE1) cleaves β-amyloid precursor protein (APP) to initiate the production of β-amyloid (Aβ), the prime culprit in Alzheimer’s disease (AD). Dysregulation of the intracellular trafficking of BACE1 may affect Aβ generation, contributing to AD pathology. In this study, we investigated whether BACE1 trafficking and BACE1-mediated APP processing/Aβ generation are affected by sorting nexin 12 (SNX12), a member of the sorting nexin (SNX) family that is involved in protein trafficking regulation.ResultsHerein, we find that SNX12 is widely expressed in brain tissues and is mainly localized in the early endosomes. Overexpression of SNX12 does not affect the steady-state levels of APP, BACE1 or γ-secretase components, but dramatically reduces the levels of Aβ, soluble APPβ and APP β-carboxyl terminal fragments. Downregulation of SNX12 has the opposite effects. Modulation of SNX12 levels does not affect γ-secretase activity or in vitro β-secretase activity. Further studies reveal that SNX12 interacts with BACE1 and downregulation of SNX12 accelerates BACE1 endocytosis and decreases steady-state level of cell surface BACE1. Finally, we find that the SNX12 protein level is dramatically decreased in the brain of AD patients as compared to that of controls.ConclusionThis study demonstrates that SNX12 can regulate the endocytosis of BACE1 through their interaction, thereby affecting β-processing of APP for Aβ production. The reduced level of SNX12 in AD brains suggests that an alteration of SNX12 may contribute to AD pathology. Therefore, inhibition of BACE1-mediated β-processing of APP by regulating SNX12 might serve as an alternative strategy in developing an AD intervention.

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Section: Resultsmentioning

confidence: 50%

Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing

Zhao

Wang

Yang

et al. 2012

Mol Neurodegeneration

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“…Cerebral cortical neurons were isolated from E18.5 Sprague-Dawley (SD) rat fetuses [28]. The brains were removed, and the neocortices were dissected out.…”

Section: Methodsmentioning

confidence: 99%

Regulation of Neurite Growth by Inorganic Pyrophosphatase 1 via JNK Dephosphorylation

et al. 2013

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Neural cell differentiation during development is controlled by multiple signaling pathways, in which protein phosphorylation and dephosphorylation play an important role. In this study, we examined the role of pyrophosphatase1 (PPA1) in neuronal differentiation using the loss and gain of function analysis. Neuronal differentiation induced by external factors was studied using a mouse neuroblastoma cell line (N1E115). The neuronal like differentiation in N1E115 cells was determined by morphological analysis based on neurite growth length. In order to analyze the loss of the PPA1 function in N1E115, si-RNA specifically targeting PPA1 was generated. To study the effect of PPA1 overexpression, an adenoviral gene vector containing the PPA1 gene was utilized to infect N1E115 cells. To address the need for pyrophosphatase activity in PPA1, D117A PPA1, which has inactive pyrophosphatase, was overexpressed in N1E115 cells. We used valproic acid (VPA) as a neuronal differentiator to examine the effect of PPA1 in actively differentiated N1E115 cells. Si-PPA1 treatment reduced the PPA1 protein level and led to enhanced neurite growth in N1E115 cells. In contrast, PPA1 overexpression suppressed neurite growth in N1E115 cells treated with VPA, whereas this effect was abolished in D117A PPA1. PPA1 knockdown enhanced the JNK phosphorylation level, and PPA1 overexpression suppressed it in N1E115 cells. It seems that recombinant PPA1 can dephosphorylate JNK while no alteration of JNK phosphorylation level was seen after treatment with recombinant PPA1 D117A. Enhanced neurite growth by PPA1 knockdown was also observed in rat cortical neurons. Thus, PPA1 may play a role in neuronal differentiation via JNK dephosphorylation.

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“…1C). Although SNX12 is widely expressed in brain (Mizutani et al, 2012;Zhao et al, 2012), it is Fig. 1.…”

Section: Introductionmentioning

confidence: 99%

Essential and selective role of SNX12 in transport of endocytic and retrograde cargo

Priya

Sugatha

Parveen

et al. 2017

Journal of Cell Science

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The endosomal protein-sorting machineries play vital roles in diverse physiologically important cellular processes. Much of the core membrane-sorting apparatus is conserved in evolution, such as retromer, which is involved in the recycling of a diverse set of cargoes via the retrograde trafficking route. Here, in an RNAi-based loss-of-function study, we identified that suppression of SNX12 leads to a severe blockage in CIM6PR (also known as IGF2R) transport and alters the morphology of the endocytic compartments. We demonstrate that SNX12 is involved in the early phase of CIM6PR transport, and mediates receptor recycling upstream of the other well-established SNX components of retromer. Ultra-structural analysis revealed that SNX12 resides on tubulo-vesicular structures, despite it lacking a BAR domain. Furthermore, we illustrate that SNX12 plays a key role in intraluminal vesicle formation and in the maturation of a subpopulation of early endosomes into late endosomes, thereby regulating selective endocytic transport of cargo for degradation. This study therefore provides evidence for the existence of early endosomal subpopulations that have differential roles in the sorting of the cargoes along endocytic degradative pathways.

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Expression of sorting nexin 12 is regulated in developing cerebral cortical neurons

Cited by 10 publications

References 25 publications

Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing

Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing

Regulation of Neurite Growth by Inorganic Pyrophosphatase 1 via JNK Dephosphorylation

Essential and selective role of SNX12 in transport of endocytic and retrograde cargo

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