Developmental and Pathological Effects of Psychosine on Oligodendrocytes of the Twitcher Mouse
2013-02-22T00:00:00Z (GMT) by
Psychosine is a lipid raft-associated cytotoxic sphingolipid that accumulates in individual nervous system affected with Krabbe disease, a deficiency of lysosomal galactosylceramidase enzyme. High levels of psychosine are believed to cause oligodendrocytes (OLs) cell death and leading to the progressive demyelination observed in these patients. The twitcher mouse (TWI) is a natural occurring mutant for this disease, which accumulates psychosine ~150 fold respect control levels and undergoes demyelination and death by the sixth week of postnatal life. Using transgenic labeling of OLs and stereological quantification, myelinating OLs are reduced in TWI spinal cord at P15 and P30. Accordingly in vivo apoptotic analysis revealed an increased OL cell death in TWI spinal cord at P15. However, at demyelination stage, the majority of apoptotic cells are activated microglia/macrophage, indicating the important involvement of immune cells in the pathology of demyelination. During prenatal and early postnatal development, psychosine has already modestly but significantly increased in TWI spinal cord. At P7, we found an unexpected increase of OLs in the cervical region of the mutant spinal cord. We hypothesized that at low concentration, psychosine might facilitate the generation of oligodendrocyte progenitors (OPCs) by modifying the lipid-raft platform for raft-associated signaling pathways. We further examined for changes in oligodendrocyte patterns and the raft-associated sonic hedgehog (SHH) pathway of TWI in the embryonic life (E10.5 to E15.5). Our results indicate distinct changes in abundance and distribution of OPCs in the embryonic spinal cord, which are concurrent with increasing levels of SHH downstream effectors. These findings are the first to show physiological levels of psychosine might affect the embryonic development of the nervous system in mutant. The relevance of these changes is still unclear but they may have profound and long lasting effects on the onset and progression of the disease. Meanwhile, our results also suggest high levels of psychosine may block the myelin formation OLs. But demyelination in mutant CNS may not be a direct result of OL cell death but be caused by immune cells reactions.