Claudin-1 and Claudin-3 as Molecular Regulators of Myelination in Leukoaraiosis Patients

Abstract

Leukoaraiosis is described as white matter lesions that are associated with cognitive dysfunction, neurodegenerative disorders, etc. Myelin depletion is a salient pathological feature of, and the loss of oligodendrocytes is one of the most robust alterations evident in, white matter degeneration. Recent studies have revealed that claudin proteins are aberrantly expressed in leukoaraiosis and regulate oligodendrocyte activity. However, the roles of claudin-1 and claudin-3 in oligodendrocytes and leukoaraiosis are still not well-defined. METHODS: Quantitative polymerase chain reaction was used to measure the expression of claudin-1 (CLDN1), claudin-3 (CLDN3), and myelinogenesis-related genes such as myelin basic protein (MBP), proteolipid protein (PLP), oligodendrocyte transcription factor 2 (OLIG2), and SRY-box transcription factor 10 (SOX10) in leukoaraiosis patients (n=122) and healthy controls (n=122). The expression of claudin-1 and claudin-3 was either ectopically silenced or augmented in Oli-neu oligodendrocytes, and colony formation, apoptosis, and migration assays were performed. Finally, the expression of myelin proteins was evaluated by western blotting. RESULTS: Our results revealed that in addition to SOX10, the expression levels of claudin-1, claudin-3, and myelinogenesis-related proteins were prominently downregulated in leukoaraiosis patients, compared to those in healthy controls. Furthermore, the growth and migration of Oli-neu cells were downregulated upon silencing claudin-1 or claudin-3. However, the overexpression of claudin-1 or claudin-3 resulted in the reduction of the degree of apoptosis in Oli-neu cells. In addition, claudin-1 and claudin-3 promoted the expression of MBP, OLIG2, PLP, and SOX10 at the translational level. CONCLUSION: Our data has demonstrated that the abnormal expression of claudin-1 and claudin-3 regulates the pathological progression of leukoaraiosis by governing the viability and myelination of oligodendrocytes. These findings provide novel insights into the regulatory mechanisms underlying the roles of claudin-1 and claudin-3 in leukoaraiosis.

Developmental Cues and Molecular Drivers in Myelinogenesis: Revisiting Early Life to Re-Evaluate the Integrity of CNS Myelin

“…Moreover, although C-X-C motif chemokine receptor (CXCR) 4, C-X-C motif chemokine ligand (CXCL) 12 and semaphorin 3F have chemoattractive effects on the OPCs migration, semaphorin 3A, CXCL1, and CXCR2 inhibit migration [ 61 , 67 , 68 ]. In addition, tenascin-c inhibited OPCs migration, whilst both claudin (CLDN) 1 and CLDN3 supported OPCs relocation, validated also in human specimens [ 59 , 69 , 70 ].…”

“…Interestingly, overexpression of inhibitor of DNA binding (ID) 2 and ID4 enhances proliferation [ 88 , 89 ]. Similarly, expression of SHH, HGF, neurotrophin-4 (NT-4), noggin, superoxide dismutase 1 (SOD1), neurotrophin-3 (NT-3), achaete-scute family bHLH transcription factor 1 (ASCL1), PAX6, CLDN1, and CLDN3 promotes the proliferation process [ 41 , 54 , 70 , 90 , 91 , 92 , 93 , 94 , 95 ].…”

“…Myelin proteolipid protein (PLP) and myelin basic protein (MBP) are the main myelin structural proteins, but it is suggested that they play an additional role in OLs differentiation [ 158 , 159 ]. CLDN1 and CLDN3 control MBP, OLIG2, PLP, and SOX10 expression: these molecules are essential for OLs differentiation, indicating that claudins are needed [ 70 ]. Finally, connexin 47 (CX47) and adenosine triphosphate binding cassette subfamily D member 1 (ABCD1) may support OLs during their differentiation, aiding in gap junction coupling and reducing oxidative stress, respectively [ 160 , 161 , 162 , 163 , 164 ].…”

“…OLs microtubule stability is mediated by MAP2 and MAPT [ 151 ], while CX32 and CX47 participate in maintenance [ 161 ]. Claudins, such as OSP, CLDN1, and CLDN3, play a pivotal role as well [ 70 , 185 ]. Transcription factors that participate in the lamellar extension process are SOX8, SOX10, NKX2-2, NKX6-2, and MYRF [ 35 , 122 , 193 , 194 ].…”