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  • Crohn s disease an inflammatory bowel disease

    2024-02-27

    Crohn’s disease, an inflammatory bowel disease that affects the gastrointestinal (GI) tract, is characterized by a polymorphism in ULK1 autophagy gene due to the presence of single nucleotide polymorphisms (SNPs). Thus, the autophagic process is impaired during the disease. The mutations in the leucine-rich domain of nucleotide oligomerizing domain-containing protein2 (NOD2) contain three mutations that are also associated with Crohn’s disease. NOD2 plays an effective role in the recruitment of ATG16L in the plasma membrane during bacterial invasion. Therefore, a mutation in NOD2 causes impairment in autophagy induction, antigen presentation, and bacterial trafficking. These defects could, therefore, cause persistence of bacterial inflammation [62]. Accumulating evidence has thus suggested autophagy to play a major role in Crohn’s disease. Genome studies have revealed the presence of SNPs in Atg genes, e.g., Atg161L, which affects the autophagic process in the disease. Atg161L plays a major role in the formation of autophagosome. Therefore, α-Amanitin of Atg161L leads to impaired autophagosome formation; moreover, in macrophages, it enhances the production of IL-1beta in response to LPS [63,64]. MAP1S has been recently identified as an autophagy-related protein that interacts with LC3 and undergoes biogenesis of autophagosomes. It has also recently been found to be significantly upregulated with an increase in autophagic flux and the activation of Wnt/beta-catenin signaling [65].
    Lysosomal storage disorders: the autophagic management issues Lysosomes are intracellular organelles with an acidic pH and play an integral role in the clearance of cellular materials and numerous other cellular processes, such as those involved in maintaining cholesterol homeostasis, degradation of cellular constituents, fighting against invading microorganisms, and plasma membrane repair. A defect in their functioning may result in lysosomal storage disorders (LSDs) manifested by the inability of the lysosomes to remove undigested molecules. Therefore, a major restraint in the cellular functions is observed in LSDs. Lysosomes have also been found to play a prominent role in an autophagic process characterized by their fusion with autophagosome followed by the digestion of its contents. Considering the profound effect that lysosomes have on autophagy, LSDs are expected to have a major impact on autophagy and vice-versa [66,67]. Various LSD models have revealed the association of defective lysosomal functioning to impaired autophagy, which includes an increase in the number of autophagosomes, reduced organelle turnover, and defective clearance of autophagic substrates. The impairment of autophagosome-lysosome fusion in LSD is attributed to the defect in the vesicular trafficking. Moreover, it is observed that the lipid composition changes during LSDs. For instance, cholesterol and sphingolipids primarily accumulate in LSDs, resulting in the formation of lipid rafts, which, in turn, affect the dynamics of the lysosomal membranes leading to the impaired fusion with the autophagosomes [66]. It has been investigated that autophagy block leads to an accumulation of toxic proteins and dysfunctional mitochondria, the consequent result of which is apoptosis. Moreover, the cells manifesting defective autophagy are prone to mitochondria-mediated apoptosis. This subject has grasped significant attention such that administration of bafilomycin A1, an attenuator of lysosomal acidification, causes blockage of autophagosome-lysosome fusion, for example, in LSDs, deciphering the role of lysosomal dysfunction as a feedback system to inhibit the fusion between autophagosome and lysosome [68]. Danon disease occurs due to the deficiency of lysosomal-associated membrane protein 2 (LAMP2). LAMP 2 has three isoforms, namely LAMP2a, LAMP2b, and LAMP2c, among which LAMP2a serves the dominating role of a receptor in chaperone-mediated autophagy. LAMP, in general, has been found to be involved in the formation of mature vacuoles from early autophagic vacuoles, suggesting the involvement of LAMP in the fusion of autophagic vacuoles with endosomes and lysosomes. Therefore, deficiency of LAMP2a disturbs the autophagic process [67]. It has been experimentally proved that LAMP1 and LAMP2 double-deficient cells delay the recruitment of RAB7, a regulator of endo-lysosomal trafficking, to the late endocytes, thereby disrupting the autophagic process [69]. Another interesting experiment demonstrated the impact of Danon disease on selective autophagy where Danon human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) demonstrated an accumulation of defective mitochondria, impaired mitochondrial flux, and an impaired mitochondrial respiratory capacity. Restoring the LAMP2a recovered all the defective mitochondrial outcomes strongly ascertaining about the association of Danon disease with impaired mitophagy [70].