Eeffects And Mechanisms Of CNS Specific Dysmyelination Induced By Cathepsin D Deficiency

Cathepsin D (CathD) deficiencies are fatal neurological diseases in human infants,sheep and mice, which are characterized by extreme loss of neurons and myelin. However,how loss of CathD leads to the defect in myelination is still unclear. In the present study,we found surprisingly a selective dysmyelination in the CNS but normal myelination in thePNS of CathD-/-mice. Being different from many other myelin-related proteins such asMBP and MAG, PLP is the most abundant protein present in CNS myelin of highervertebrates, and is only found in the CNS myelin. PLP plays an important role in thematuration and polarization of oligodendrocytes, and the formation and/or maintenance ofmultilayer myelin. Thus, we further examined the intensity of the Fluoromyelin Green andPLP staining in corpus callosum of CathD-/-mice at P7, P14and P24. It is found that therewas less extent of increase in the level of Fluoromyelin Green staining and PLP expressionwith the increase of age, compared with that in CathD+/+mice, indicating a significantimpairment of the expression of this CNS spesicif myelin ptorein. Interestingly, PLP werefound to be accumulated around the nucleus in the oligodendrocyte lineage cells (OLs) ofCathD-/-mice, while they have been normally dilevered to the plasma membranes of thatcells in CathD+/+mice. It is also found that the number of mature oligodendrocytes (CC1+)in the corpus callosum of P14and P24CathD-/-mice was significantly lower than that inCathD+/+mice, while there was no difference at P7, and the number of OPCs (NG2+) wascomparable, suggesting that CathD deficiency only resulted in a delay of myelination andoligodendrocyte maturation without affecting tho OPC specification and migration. Byusing in vitro cultured OPCs, we found that CathD deficiency could induce a defect in thetrafficking of PLP from Late endosome/Lysosome (LEs/Ls) to the plasma membrane ofOLs, as more PLP was shown to gather in LEs/Ls around nucleus in OLs from CathD-/-mice. Moreover, CathD, PLP, and VAMP-7were detected to interact with each other,suggesting that VAMP-7might be involved in the process of PLP trafficking, and cause thedelay of oligodendrocyte maturation and myelination. Together, our results indicats that inaddition to its well known proteolysis activity, CathD may also play a crucial role in theoligodendrocyte maturation and myelination by means of protein-protein interaction.