Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis

Abstract

Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in multiple sclerosis (MS) is associated with neurodegeneration and clinical worsening. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that Gsta4 loss impairs differentiation into myelinating OLs in vitro. In addition, we identify Gsta4 as a target of both dimethyl fumarate, an existing MS therapy, and clemastine fumarate, a candidate remyelinating agent in MS. Overexpression of Gsta4 reduces expression of Fas and activity of the mitochondria-associated Casp8-Bid-axis in adult oligodendrocyte precursor cells, leading to improved OL survival during differentiation. The Gsta4 effect on apoptosis during adult OL differentiation was corroborated in vivo in both lysolecithin-induced demyelination and experimental autoimmune encephalomyelitis models, where Casp8 activity was reduced in Gsta4-overexpressing OLs. Our results identify Gsta4 as an intrinsic regulator of OL differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies.

Axonal mitochondria adjust in size depending on g‐ratio of surrounding myelin during homeostasis and advanced remyelination

“…Experimental details for our material are summarized in Table 2. Lysolecithin injections in the cervical spinal cord were performed as previously described (Blakemore & Franklin, 2008; Carlström et al., 2020; Ineichen et al., 2017): briefly, rats were deeply anesthetized under fentanyl, medetomidine, and midazolam (for Lewis rats) or isoflurane (for Dark agouti rats). Lysolecithin solution (1% in injectable water) was stereotactically injected to either the dorsal funiculus of the cervical spinal cord level C3 (Lewis) or the CC (Dark agouti).…”

Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders

“…Besides the intracellular threats, extracellular ROS released by pro-inflammatory cells, such as microglia and macrophages, can attack neighbouring OPCs/oligodendrocytes [106,107]. It is important to note that the effect of ROS in circulating or infiltrating immune cells depends on the site of production, especially in case of autoimmunity where ROS induce Treg activation while limiting T cell proliferation and cytokine production [108][109][110][111], resulting in dampened disease activity. Similarly, increased ROS generation by peripheral blood monocytes via NOX3 is associated with better response to dimethyl fumarate in MS patients.…”

“…The GST ∏ isoenzyme has been detected as a marker for mature oligodendrocytes that is absent in OPCs [147][148][149]. Moreover, recent studies identified an additional isoenzyme, GSTα4, to do play a role in OPC differentiation and protection against HNE [109]. In line with possessing a threefold lower basal level of GSH compared to astrocytes, OPCs are more vulnerable to GSH depletion [141,150,151].…”

“…Similarly, increased ROS generation by peripheral blood monocytes via NOX3 is associated with better response to dimethyl fumarate in MS patients. Within the CNS parenchyma, however, ROS production is frequently linked to tissue injury [ 108 , 109 ]. Acute inflammatory activity of microglia and infiltrated macrophages causes an oxidative burst, but chronic low-grade microglia/astrocyte activation is also a frequent characteristic of neurological disease.…”

Current and emerging disease‐modulatory therapies and treatment targets for multiple sclerosis

“…In two placebo-controlled phase III trials, 240 mg of DMF taken twice daily reduced ARR with 45 and 53%, respectively [127,128]. The mechanism of action of DMF includes effects on nuclear factor erythroid 2related factor 2, a transcription factor involved in cellular redox reactions, and an increase in oxidative responses in myeloid cells, in turn downregulating activated lymphocytes [66,129]. Flushing, abdominal pain, diarrhoea and nausea are common and have a negative effect on tolerability.…”