PROGRAMMED CELL-DEATH IN THE DYSMYELINATING MUTANTS

A large number of genetic mutants that are missing a particular myelin protein or that have an aberrant myelin protein composition have been described. These mutations usually cause dysmyelination in the PNS or CNS. Similarly, the nervous system of animals experimentally altered to block synthesis of myelin proteins have recently been generated that show aberrations in the myelin sheath. For both groups of animals, the numbers of myelinating cells remain relatively stable and glial cell death is minimal. The exception is animals with mutations in the proteolipid protein (PLP) gene which exhibit extensive death of oligodendrocytes (OLs). The degree of OL death in the PLP mutants generally correlates with the amount of dysmyelination. Dying OLs in the PLP mutants exhibit the classical features of apoptotic cells. Programmed cell death (PCD) is often, but not necessarily, manifested by cleavage of DNA into abundant oligonucleosomal fragments. Detection of these abundant DNA fragments was examined in normal and jimpy (jp) mice using the TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) method. In normal spinal cord and brain, at least twice as many cells exhibited DNA fragmentation when compared to numbers of pyknotic glia observed microscopically. In jp spinal cord and brain, roughly one-half of cells exhibited DNA fragmentation when compared to numbers of pyknotic glia observed microscopically. PCD of cells in normal development involving DNA fragmentation has been previously described and our results support that conclusion. The data obtained from the jp mice suggests that the mechanism of apoptosis due to PLP mutations is somewhat different from that which occurs in normal development.