**5.6 Taysach's disease and protein misfolding**

Lysosomal storage diseases (LSDs) are comprised magnificence group of rare diseases of numerous pathologies. Their distinctive characteristics include dysfunction of the endosome–lysosome system, which in lots of instances ends in the accumulation of toxic metabolites and death at molecular level. A subset of LSD includes GM2 gangliosidoses. GM2 gangliosidoses are a series of associated disorders resulting from insufficiency of active β-hexosaminidase A (HexA). HexA enzyme processes GM2 ganglioside to GM3 ganglioside in the lysosome. Inactivation or loss of HexA causes toxic metabolite buildup of GM2, leading to disease formation and cell death. Tay–Sachs disease (TSD) is clinically described with the aid of using mutations with HEXA gene. The HexA enzyme is made from the HEXA and HEXB genes, which encode α and β subunits, respectively with 60% similarity on the amino acid. They are synthesized on the endoplasmic reticulum (ER), wherein they are glycosylated and form intramolecular disulfide linkages and dimerize. The structural similarities among the chains form more than one isozyme through differential affiliation such as HexA (αβ), HexS (αα), and HexB (ββ). HexB is the most stable of the complexes and HexA is the only species capable of processing GM2 ganglioside. This led to hypothesis development stating low β production promotes heterodimerization over β homodimerization. In the Golgi apparatus, specific glycans are modified with mannose 6-phosphate (M6P), allowing for the trafficking of Hex enzymes to lysosomes. In the lysosome, presentation of the GM2 ganglioside substrate from the bilayer to the active site of HexA additionally requires the adaptor protein GM2-activator. Loss of function in either subunit of HexA or its adaptor protein can lead to GM2 gangliosidosis [63].

### **5.7 Miscellaneous conditions due to protein misfolding**

#### *5.7.1 Hypoxia*

Hypoxia induces UPR at several targets, including airway epithelial cells and the mechanisms by which this occurs are not fully understood. Therefore, there are several ways, in which hypoxia can cause ER and UPR stress. First of all, reactive oxygen species formed under hypoxia can modulate UPR activation by directly or indirectly affecting BiP and interfering with the formation of disulfide bonds [64]. Redox-sensitive PDI chaperones are restored during protein folding. It is reduced by electron transfer to ER oxido-reduction (ERO1), which then requires molecular oxygen for reoxidation and restoration of function. In addition, since ERO1 is a target of hypoxia-inducing factor (HIF), hypoxia may modulate disulfide bond formation in several ways.

### *5.7.2 Idiopathic pulmonary fibrosis*

Idiopathic pulmonary fibrosis (IPF) is a scarring disease histologically characterized by the presence of fibroblastic lesions. Despite antifibrotic therapy, the prognosis is grave. Fewer researchers have shown that ER stress plays an important role; however, the biological mechanisms that cause the condition are still unclear. Alveolar type II (AT2) cells secrete surfactant protein C (SFTPC) and mutations in surfactant protein C (SFTPC) are associated with familial IPF and profound UPR activation. Many of these mutations disrupt the BRICHOS SFTPC domain, which acts as a distinct chaperone to promote SFTPC folding. Infringement of SFTPC folding can lead to protein aggregation and activation of all UPR cancers. In a mouse model, these mutations interfere with lung morphogenesis, either directly leading to fibrosis or increasing the lung's sensitivity to secondary infections that lead to pulmonary fibrosis [62].

## *5.7.3 Cataract*

Cataract is defined as a clouding of the transparent lens inside the eye, reducing the amount of light and subsequently reducing vision. The natural lens is a crystalline substance and the precise structure of water and protein creates a clear pathway for light to pass through. Crystallin, the major protein of the mammalian eye lens, exists in the α-polydisperse B-crystallin form, and each with a molecular weight of approximately 20 kDa. Members of the alpha (α) and β γ crystallin family are the major soluble lens proteins. Α- crystalline is an ATP-independent chaperone that effectively binds to damaged or partially unfolded proteins and dissociates them to prevent large-scale protein aggregation. Α- crystalline comprises of αA and αB subunits and belongs to family of heat shock proteins [34, 65, 66]. Αlpha-crystallin depends on external conditions, such as pH and temperature, quaternary structure, ionic strength, and concentration [67]. In addition to the lens, it is widely found in many other tissues, including the brain, lung, spleen, heart, and skeletal muscle, where it acts as a chaperone and interacts with several partially folded target proteins. Alpha-crystallins prohibit the formation and precipitation of αB- and α-crystallin, as well as ordered protein aggregates (amyloid fibrils).

Proteomic analysis of lens proteins revealed deamidation, oxidation, glycosylation, and shortening as various factors associated with damage. Deamidation is one of the most common damages to crystallins, introducing a negative charge to proteins by converting residues of glutamine to glutamate. Asparagine is also susceptible to

deamidation, and both residues are transformed into cataract aggregates. Several oxidation sites targeting tryptophan, cysteine, and methionine residues have been identified in crystallin. Deamination decreases the stability of βA3 and βB1 crystallins and increases the tendency to aggregation. Destabilization, due to lifetime accumulation of covalent modifications/alteration, can lead to partial unfolding of proteins, which can lead to the formation of intermediate conformations exposing previously hidden hydrophobic residues. Hence, proving that destabilization of the native state of the lens protein due to covalent bond damage leads to aggregation [66].
