Introduction

Alzheimer’s disease is a recognized public health priority because it imposes heavy costs on health care and economic systems [1]. Alzheimer’s is a neurodegenerative diseasهe known as the most common form of dementia and affects approximately 46 million people worldwide [2]. Endoplasmic Reticulum (ER) dysfunction has been observed in various human diseases such as Alzheimer’s, Parkinson’s and Huntington’s [9]. ER function and its morphology are associated with autophagy [6]. It has recently been shown that ER stress causes autophagy [14]. Autophagy is essential for maintaining tissue homeostasis and prevents the onset and progression of many diseases such as aging, neurodegenerative diseases and cancer [15]. Autophagy is a process that occurs in most cells, which is responsible for degrading improperly folded proteins and organs damaged by lysosomes [16]. Autophagy is associated with neurodegenerative diseases such as Alzheimer’s [17] and it has also been shown that Alzheimer’s disease interferes with the autophagy process [18]. In autophagy, when there is stress, an autophagosome is formed that contains portions of ER proteins. Autophagy that occurs in the endoplasmic reticulum network is known as selective autophagic removal of ER (ER-phagy) and balances the flexibility of the ER network during the response of unfolded proteins, aiding cellular homeostasis [19]. ER-phagy involves the breakdown of proteins in the cysternae of the ER network within the autophagosomes. In mammals, there are four receptors for ER-phagy which are basically proteins living in the ER network or transmembrane which are: ER ‐phagy receptor 1 (FAM 134B), cell cycle progression 1 (CCPG1), SEC62 homolog, and reticulon 3 (RTN3).

Materials and Methods

In this study, data were extracted from the GEO (Gene Expression Omnibus) database [24] by using the keyword “Alzheimer’s disease”. Only those studies conducted on transgenic mice were selected and unrelated and pharmacological studies were excluded. To analyze data, GEO2R online software and Benjamini & Hochberg method were used, and the significance level was set at 0.05 [25]. STRING database was used to predict protein interactions. In this regard, for the genes NPC1, FAM134B, SEC62, RTN3 and CCPG1, protein interactions were predicted and drawn. Separate protein interactions for FAM134B and NPC1 genes were also evaluated [25].

Results

Nine studies that had compared gene expression on non-transgenic (wild) mice and Alzheimer’s models were finally selected, and the data from these studies were analyzed in GEO2R online software and gene expression changes were recorded. The results of the genes involved in ER-phagy showed fusion expressions in different models of Alzheimer’s disease. An increase in the expression of genes such as the FAM134B gene was observed in studies with reported mutations in microtubule-associated protein tau (MAPT) and amyloid precursor protein (APP) genes. An increase in the NPC1 gene was observed in two studies that had reported mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and MAPT genes. The SEC62 and CCPG1 genes both showed a decrease in expression in one study. The RTN3 gene did not show significant expression in any of the studies. Protein interactions for the study genes are illustrated in Figure 1.

After the expression of FAM134B gene was increased in GSE53480 and GSE31372 studies, the genes of proteins related to it were also examined. In the GSE53480 study, the Wnk1 gene expression increased and the Sbf2 gene expression decreased, and in the GSE31372 study, the Map1lc3b gene showed an increase in expression (Table 1).

For the NPC1 gene, which had a reported expression increase in the GSE60460 and GSE36981 studies, NPC1-related protein genes were also examined. In the GSE60460 study, the Abcg1 gene showed an increase in expression and the Srebf2 gene showed a decrease in expression, and in the GSE36981 study, the Osbpl5 gene showed a decrease in expression (Table 2).

Discussion

Recent studies suggest that the ER-phagy process plays the most important role in maintaining the shape and function of ER [20]. One of the ER functions is to control the quality of proteins. Recently, however, it has been observed that under stress, a part of the ER membrane along with its proteins are transferred to the lysosome and then removed. This stress can include: drug-induced stress, overall cell stress, or hunger [28]. The ER-phagy process has been shown to be dependent on the process of response to unfolded proteins [29]. Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, etc. have also been shown to be associated with the process of responding to unfolded proteins [30]. In this regard, we investigated the relationship between the expression of genes involved in ER-phagy in Alzheimer’s disease. Since FAM134B, NPC1, SEC62, CCPG1 AND RTN3 genes are important ER-phagy genes, their expression in Alzheimer’s models was investigated. However, only in 4 of the 9 selected studies for review showed increased expression in only two genes, FAM134B and NPC1. These data indicate that the expression of ER-phagy genes does not change much in Alzheimer’s disease. Since only FAM134B and NPC1 genes showed increased expression, these genes seemed to have a function other than ER-phagy. Therefore, changes in the expression of the genes of the proteins associated with these two proteins were also examined. The FAM134B gene showed increased expression in two studies; one in the hippocampal region along with Wnk1 gene and one in the forebrain along with the Map1lc3b gene. Moreover, with increased expression of NPC1 in the subventricular zone, an increase was also observed in the Abcg1 gene expression (Figures 2 and 3).

 

Conclusion

Of the genes involved in ER-phagy, only two genes, FAM134B and NPC1, may be involved in Alzheimer’s disease. The FAM134B gene seems to interact with the Wnk1 gene, , which plays a role in cell survival and proliferation, in the hippocampus and forebrain. The FAM134B gene may also interact with the Map1lc3b gene, which has a role in removing phagosomes and ubiquitizing proteins, in the forebrain. Furthermore, NPC1 seems to interact with the Abcg1 gene, which activates lipid homeostasis, in the subventricular zone.

Ethical Considerations

Compliance with ethical guidelines

All ethical principles were considered in this article. 

Funding

University of Zabol financially supported this research (Code: 9618-59).

Authors' contributions

Drafting the manuscript: All authors; Literature review, data visualization: Zaliye Gharib; Editing the manuscript, supervision: Nima Sanadgol, Naser Sanchooli.

Conflicts of interest

The authors declared no conflict of interest.

Acknowledgements

The authors would like to thank the University of Zabol for their financial support of this study.

 

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