GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review

Abstract

Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc3Man9GlcNAc2 highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.

ERVW-1 Activates ATF6-Mediated Unfolded Protein Response by Decreasing GANAB in Recent-Onset Schizophrenia

“…GANAB is a catalytic subunit of glucosidase II [ 17 ]. GANAB activates ATF6 and later leads to MS [ 111 ]. However, there are no available studies on the mechanism of GANAB in schizophrenia.…”

Multi-Criterial Model for Weighting Biological Risk Factors in Multiple Sclerosis: Clinical and Health Insurance Implications

“…Epidemiological and NGS studies have found that age, family kinship, and some genetic markers, such as HLA 1501, are elements of susceptibility to getting sick [16,30]. Biological observations have indicated some interesting molecules, including vitamin D [26,39], Neurofilament light (NfL) [40,41], IFP35, and GANAB [42][43][44][45] as emerging biomarkers in demyelinating diseases. Each of these variables has been deeply studied in MS literature, but their resulting effects on getting sick when they are coincident is still lacking and unquantified.…”

Potential Crosstalk between the PACAP/VIP Neuropeptide System and Endoplasmic Reticulum Stress—Relevance to Multiple Sclerosis Pathophysiology

“…Glucosidase II is an enzyme involved in the processing of N-linked glycans during protein folding in the ER and its alpha subunit (GANAB) is involved in the activation of the UPR [46,47]; its effects involve the promotion of mRNA disintegration via the IRE1dependent pathway. Importantly, clinical studies conducted in human peripheral blood mononuclear cells (PBMCs) demonstrated a downregulation of GANAB in interferon (IFN)β-treated humans compared to untreated controls, and an even greater GANAB downregulation in IFNβ treatment-responsive patients, thereby identifying this UPR mediator as a suitable biomarker for MS [46].…”

“…Post-mortem analyses of human CNS tissues have demonstrated the presence of activated IRE1α and UPR in patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) [47]. However, serum levels of CHOP appeared to be similar in human RRMS patients compared to healthy controls [48].…”