Graded oligodendrocyte vulnerability is regulated by the transcription factor DNA-damage inducible transcript 3 (DDIT3)

Oligodendrocytes are integral to efficient neuronal signaling. Loss of myelinating oligodendrocytes is a central feature of many neurological diseases, among multiple sclerosis. Results of neuropathological studies suggest that oligodendrocytes react with differing sensitivity to toxic insults, with some cells dying early during lesion development and some cells being resistant for even weeks. Such a proposed graded vulnerability has never been demonstrated but provides an attractive window for therapeutic interventions. Beyond, biochemical pathways associated with graded oligodendrocyte vulnerability are not well explored.
By immunohistochemistry and serial block-face scanning electron microscopy (3D-EM) we show that cuprizone-induced metabolic stress results in an “out of phase” degeneration of oligodendrocytes. While the expression induction of stress response transcriptions factors, specifically in oligodendrocytes, occurs within days, subsequent oligodendrocyte apoptosis is a process going on for weeks. In line with the idea of an out of phase degeneration of oligodendrocytes, detailed ultrastructural reconstructions of the axon-myelin unit demonstrate demyelination of single internodes. Genome wide array analysis revealed an active unfolded protein response early after initiation of cuprizone intoxication. Besides cytoprotective pathways, the pro-apoptotic transcription factor DNA-damage-inducible transcript 3 (DDIT3) was induced selectively in the vulnerable oligodendrocyte population. Besides the amelioration of toxin-induced oligodendrocyte apoptosis, demyelination, microgliosis, astrocytosis and acute axonal damage were less intense in Ddit3-null mutants.
This study identifies activation of an endoplasmic reticulum stress cascade in oligodendrocytes as an important regulator of a graded vulnerability of this cell population. Interference with such endoplasmic reticulum stress cascades offers a promising therapeutic approach for demyelinating disorders.