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. 2018 May 31;12:339. doi: 10.3389/fnins.2018.00339

Figure 1.

Figure 1

Chronic Cerebral Hypoperfusion (CCH) induces protein misfolding in the context of Metabolic Syndrome (MetS). Under cell stress, proteostasis network surveillance systems refold or degrade proteins through several mechanisms. Accumulation of misfolded proteins in the Endoplasmic Reticulum (ER) triggers the unfolded protein response (UPR) which induces an upregulation in the expression of chaperone genes. This response is characterized by transcription factor 6 (ATF6), inositol-requiring enzyme 1a (IRE1-α) and X box–binding protein 1 (Xbp1). These ER stress components trigger ER-associated degradation (ERAD) genes, which work to restore organelle function and maintain cell survival. Under ER stress, protein RNA-like ER kinase (PERK) mediates the phosphorylation of eukaryotic translation initiator factor 2α (eIF2α), which inhibits translation and attenuates protein synthesis at the ER. Prolonged ER stress increases levels of intracellular calcium, activating signals of cell death. Mitochondria responds to cell stress throughout its own protein quality control system known as UPR(mt), promoting transcription of mitochondrial chaperones and factors for organelle homeostasis. Depending on the nature, size and solubility of substrates, misfolded proteins can also be degraded by the Ubiquitin Proteasome System (UPS), Chaperone Mediated Autophagy (CMA) or macroautophagy. In general, most soluble and monomeric misfolded proteins are degraded by the UPS and CMA. Substrates targeted by CMA are bound by chaperone heat-shock cognate 70 (Hsc70) and degraded into amino acids by lysosomal hydrolases. Misfolded proteins in the cytosol are also conjugated to ubiquitin through an enzymatic cascade involving the ubiquitin-activating (E1), ubiquitin-conjugating (E2), and ubiquitin-protein (E3) enzymes. Then, ubiquitinated substrates are degraded by the proteasome. Other substrates, such as protein aggregates, are recognized by molecular chaperones, ubiquitinated and delivered to the autophagosome via Beclin-1 complex. The autophagosomes are fused with lysosomes to form autolysosomes, where misfolded proteins are degraded. Agents targeting proteostasis network pathways in CCH-induced protein misfolding are shown in blue color text. N-stearoyl- L-tyrosine (NSTyr), Lipoxin A4 methyl ester (LXA4 ME).