Cuprizone‐induced graded oligodendrocyte vulnerability is regulated by the transcription factor DNA damage‐inducible transcript 3

Abstract

Oligodendrocytes are integral to efficient neuronal signaling. Loss of myelinating oligodendrocytes is a central feature of many neurological diseases, including multiple sclerosis (MS). The 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 weeks. This proposed graded vulnerability has never been demonstrated but provides an attractive window for therapeutic interventions. Furthermore, the biochemical pathways associated with graded oligodendrocyte vulnerability have not been well explored. We used immunohistochemistry and serial block‐face scanning electron microscopy (3D‐SEM) to show that cuprizone‐induced metabolic stress results in an “out of phase” degeneration of oligodendrocytes. Although expression induction of stress response transcription factors in oligodendrocytes occurs within days, subsequent oligodendrocyte apoptosis continues 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. In parallel, genome wide array analyses revealed an active unfolded protein response early after initiation of the cuprizone intoxication. In addition to the cytoprotective pathways, the pro‐apoptotic transcription factor DNA damage‐inducible transcript 3 (DDIT3) was induced early in oligodendrocytes. In advanced lesions, DDIT3 was as well expressed by activated astrocytes. Toxin‐induced oligodendrocyte apoptosis, demyelination, microgliosis, astrocytosis, and acute axonal damage were less intense in the Ddit3‐null mutants. This study identifies DDIT3 as an important regulator of graded oligodendrocyte vulnerability in a MS animal model. Interference with this stress cascade might offer a promising therapeutic approach for demyelinating disorders.

Guanabenz modulates microglia and macrophages during demyelination

“…We further assessed the effectiveness of Gz in a toxin-induced model of demyelination to contrast the severe CNS inflammation in EAE. The cuprizone model, which induces selective oligodendrocyte cell death 28,34 , was chosen as there is evidence that oligodendrocyte viability during exposure to cuprizone is dependent on the ISR pathway 35,36 . Surprisingly, we did not observe a significant increase in oligodendrocyte numbers in Gz-treated mice compared to saline-treated animals after the withdrawal of cuprizone (but continuous infusion/presence of Gz).…”

Mechanism of Siponimod: Anti-Inflammatory and Neuroprotective Mode of Action

“…For example, sex steroids such as 17β-estradiol have been shown to mediate both, neuroprotective and anti-inflammatory effects during EAE [92]. Additionally, endoplasmic reticulum stress responses have been shown to mediate both, toxin-induced oligodendrocyte degeneration [93], T cell differentiation [94] or apoptosis [95].…”

Oligodendrocyte degeneration and concomitant microglia activation directs peripheral immune cells into the forebrain

“…However, we did not find any evidence of demyelination at week 1 on the histochemical and immunohistochemical level (see figure 1). In a recent paper we were able to demonstrate that cuprizoneinduced oligodendrocyte apoptosis is paralleled by the activation of the endoplasmic-reticulum stress response (Fischbach, Nedelcu et al 2018). One component of the endoplasmic-reticulum stress response is the selective and regulated degradation of mRNA, termed regulated IRE1-dependent decay (RIDD), which relieves endoplasmic-reticulum stress by reducing the amount of the endoplasmic-reticulum protein load.…”