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) are associated with disease progression but the underlying mechanism are elusive. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that its loss prevents differentiation into myelinating OLs. Also, Gsta4 appeared to be a novel target for Clemastine, in clinical trial for MS. Over-expression of Gsta4 reduced the expression of Fas and activity along the 2 mitochondria-associated Casp8/Bid-axis in adult pre-OLs from the corpus callosum, together promoting enhanced pre-OL survival during differentiation. The Gsta4-mediated input on apoptosis during adult OL differentiation was further verified in the LPC and EAE model, where Casp8 were reduced in pre-OLs with high Gsta4 expression in an immune responseindependent fashion. Our results place Gsta4 as a key regulator of intrinsic mechanisms beneficial for OL differentiation and remyelination, and as a possible target for future MS therapies. IntroductionOligodendrocyte precursor cells (OPC) and oligodendrocytes (OL) are abundant throughout the central nervous system (CNS). They serve important roles in preserving the functionality and integrity of neuronal network connections, including providing metabolic support and enabling axonal signal transmission along myelinated fibers 1-4 . OLs are affected directly or indirectly in many CNS diseases, of which Multiple Sclerosis (MS) is one of the most widely studied 5 . Despite findings of proliferating OPCs around lesions 6,7 , OLs fail to remyelinate axons 8-12 which leads to neurodegeneration 9,13-15 .Previous studies have indicated that as many as 50% of pre-OLs undergo programmed cell death during development and 20-30% during post-natal conditions 16,17 . Recent studies have also shown mechanisms of OLs loss during development 18,19 , similar approached in postnatal animals and adult OLs are lacking.3 Remyelination do occur in adulthood 6,20-23 , but the time interval within which the OLs should receive crucial support in order to survive is restricted [24][25][26] .The OPCs capacity to remyelinate is strongly diminished over-time [27][28][29] and differentiating cells are exposed to considerable cellular stress [30][31][32][33] . Interestingly, mitochondrial function and the capacity to scavenge endogenous toxins are also diminished with ageing and diseaseprocesses such as those present in MS [34][35][36] . Notably, the activity of the primary sensor of cellular stress, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), is also diminished with ageing 37,38 . Dysfunctional mitochondria and toxin scavenging induce lipid peroxidation (LPO) of unsaturated lipids in membranes, against which OLs are particularly vulnerable to [39][40][41][42] . Upon LPO, reactive aldehydes, such as 4-Hydroxynonenal (4-HNE), will be generated and diffuse in the cytosol, unless scavenged by conjugation to glutathione. If not scavenged, 4-HNE will bind to macro-molecules and...

Clemastine Inhibits the Biofilm and Hemolytic of Staphylococcus aureus through the GdpP Protein

“… S. aureus has become one of the major causes involved in a wide range of community- or hospital-acquired infections. Chronic or persistent S. aureus infection has posed a serious threat to human health due to recalcitrant biofilms formation which is highly tolerant of traditional antibiotics ( 24 , 25 ). Clemastine is one of the first-generation antihistamines with slight side effects, such as drowsiness.…”

“…Clemastine is one of the first-generation antihistamines with slight side effects, such as drowsiness. Recent studies found clemastine might be used as the remyelinating therapy of multiple sclerosis and seldom reports have demonstrated the inhibition of clemastine on the multiple growth stages of plasmodium parasite and mycobacterial growth ( 25 – 27 ). These studies strongly suggest the complicated physiological function of clemastine against a variety of human diseases, while data from studies addressing clemastine for the chemotherapy of S. aureus infection are still lacking.…”