**2. Endoplasmic reticulum stress**

As we mentioned earlier, increased metabolic demand, infection, hypoxia, excessive lipid accumulation, genetic disorders, and various toxins can disrupt ER homeostasis and cause ER stress due to misfolded or unfolded protein accumulation [6]. To reduce ER stress, a signaling pathway called the unfolded protein response (UPR) is activated, which slows protein synthesis and increases protein degradation [7, 8]. Activated UPR creates a stress response via protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) [9, 10], inositol-requiring enzyme 1 (IRE-1) [10–12], and activating transcription factor 6 (ATF-6) [13, 14]. IRE1 acts by activating Jun N-terminal kinase (JNK) [15]. ATF-6 increases the expression of the X-box binding protein 1 (XBP-1s) factor in the nucleus [16]. XBP-1s binds to some genes containing DNA regions, and in ER expansion, folding capacity is increased. It stimulates the transcription of genes involved in the ER-related degradation pathway and the activation of the ER-related degradation pathway, and the demand load on the ER is alleviated. With this mechanism, unfolded proteins are degraded. When this function fails, the ER activates the nuclear factor kappa B (NF-kB) to produce a signal in the cell [15]. After this signal, some apoptotic genes are stimulated and apoptosis is triggered by the stimulated genes.

### **2.1 Activation of PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase)**

PERK activation plays an important role in ER stress [17]. PERK has a specific binding site for GRP78, a chaperone involved in protein folding known as 78-kDa glucoseregulated protein (GRP78/BIP) [18]. After unfolded or misfolded proteins accumulate in the lumen, GRP78 separates from PERK and causes PERK to oligomerize [19]. Then, PERK activates itself. Then, PERK phosphorylates eukaryotic initiation factor 2 (eIF2α) [20]. While eIF2α is phosphorylated, it remains bound to eIF2B, which acts as GEF, thus preventing the formation of the translation initiation complex eIF2α/GTP/Met-tRNAi [21]. Phosphorylation of eIF2α under ER stress stimulates the translation of the transcription factor ATF-4, which plays a role in the ER stress response [18].

*The Relationship of Some Neurodegenerative Diseases with Endoplasmic Reticulum Stress… DOI: http://dx.doi.org/10.5772/intechopen.111693*

#### **2.2 Activation of ATF-6 (activating transcription factor-6)**

ATF-6 is a trans-membrane protein involved in ER stress [22]. After protein folding in the ER is inhibited, ATF-6 migrates to the Golgi apparatus. GRP78 is involved in this event [23]. There are GLS1 and GLS2 structures on ATF-6, which are involved in adhesion to the Golgi [24]. When GRP78 is bound to GLS1, it retains ATF-6 in the ER membrane [25]. If there is unfolded protein in the lumen, GRP78 dissociates from GLS1, and thus GLS2 is activated and migrates to ATF-6 Golgi [13]. In the Golgi, the transmembrane region of ATF-6 is cut, and eventually, the systolic bZIP region of ATF-6 travels to the nucleus and stimulates the transcription of XBP-1 [14]. The XBP-1s form of XBP-1 stimulates the transcriptional responses of the UPR. Thus, it reduces long-term ER stress [25].

#### **2.3 Activation of IRE-1 (inositol-requiring enzyme 1)**

IRE-1 is an ER transmembrane protein. In the ER stress state, IRE-1 is activated due to the cleavage of GRP78 and stimulates XBP-1 activation [26]. This stimulates the activation of XBP-1 s. XBP-1 s play a role in the differentiation of cells by increasing the transcription of genes responsible for ER expansion so that cells can respond to the increased demands of protein synthesis and modification [15]. XBP-1s travels to the nucleus and upregulates the transcription of genes involved in phospholipid synthesis, which drives ER-related degradation and expansion [27]. It also plays a role in the activation of IRE-1 and the activation of the JNK signaling pathway [28]. IRE-1 interacts with TNF receptor-associated factor 2 (TRAF2), activating its downstream signaling. TRAF2 then binds to ASK1, and ASK1 phosphorylates and activates JNK [26]. This effect of IRE-1 provides a bridge between ER stress, growth factors, and mitogens [15] (**Figure 1**).

#### **2.4 ER functions and relations with organelles**

The endoplasmic reticulum (ER) is a cytoplasmic organelle responsible for cytoplasmic protein synthesis [30]. The ER has many vital cellular functions, such as lipid and steroid synthesis, Ca2+ homeostasis and storage, carbohydrate metabolism, and protein synthesis [31]. With these features, the ER provides internal connection and coordination with other organelles and many proteins and physical structures in the cell. Therefore, they are in multiple contacts with all membrane-bound organelles, including the ER, plasma membrane (PM), mitochondria, Golgi, endosomes, and peroxisomes [30].

#### **2.5 ER and plasma membrane (PM)**

The ER acts as a Ca2+ store in the cell and has dynamic communication with the PM. Contact sites between ER and PM play a role in Ca2+ exchange. At ER-PM junctions, stromal interacting molecule (STIM) proteins sense a decrease in ER Ca2+ levels, undergo a conformational change along the ER that repositions tubular structures to ER-PM, and directly activate Orai, the pore-forming component of Ca2 + −. The release-activated Ca2 + (CRAC) channel triggers channel opening and Ca2+ influx [32]. In addition, ER-PM contact sites are important for phosphatidylinositol metabolism, particularly for the regulation of the lipid signaling molecule phosphatidylinositol 4-phosphate (PI4P) [30].

**Figure 1.** *Effective pathways in the ER stress response [29].*
