Abnormal Ca 2+ regulation in oligodendrocytes from the dysmyelinating jimpy mouse

Abstract

Jimpy (jp) is a point mutation in the gene on the X chromosome which codes for the major myelin proteolipid protein. Most oligodendrocytes (OLs) in the jp mouse undergo cell death at the time when they should be actively myelinating. Loss of mature OLs results in severe CNS dysmyelination. Dying jp OLs have the morphology of apoptotic cells but it is not clear how the mutation activates biochemical pathways which lead to programmed death of OLs in jp CNS. There is compelling evidence from a number of systems that high levels of intracellular Ca 2+ ([Ca 2+] i) can activate downstream processes which result in both apoptotic and necrotic cell death. To determine whether [Ca 2+] i dysregulation might be involved in the death of jp OLs, we used ratiometric imaging to determine levels of [Ca 2+] i in OLs cultured from jp and normal CNS and in immortalized cell lines derived from jp and normal OLs. Immortalized jp OLs and OLs isolated directly from jp brain both showed a similar elevation in [Ca 2+] i ranging from 60% to 150% over control values. A higher baseline [Ca 2+] i in jp OLs might increase their vulnerability to other insults due to abnormal protein processing or changes in signaling pathways which act as a final trigger for cell death.