A protein known as Gsta4 is critical in the growth and activity of oligodendrocytes, a special type of brain cell that generates the myelin sheath that is damaged in multiple sclerosis (MS), a study shows.
The overproduction of Gsta4 in a MS rat model led to milder disease and lower disability scores compared to healthy rats. The authors suggest that Gsta4 may be an important therapeutic target for the development of reparative MS therapies.
The study, “Gsta4 controls apoptosis of differentiating adult oligodendrocytes during homeostasis and remyelination via the mitochondria-associated Fas-Casp8-Bid-axis,” was published in the journal Nature Communications.
MS is caused by the immune system attacking the myelin sheath, the protective coating that covers nerve fibers. Myelin is generated and maintained by cells called oligodendrocytes.
In the early stages of MS, oligodendrocytes mature from oligodendrocyte precursor cells (OPCs), creating new myelin (remyelination), which restores and maintains nerve cell function. However, over time, the formation of new oligodendrocytes is reduced along with the ability to remyelinate nerve fibers.
So far, the underlying mechanisms of this process remain unknown.
Now, researchers at the Karolinska Institutet in Sweden investigated these mechanisms to better understand the loss of oligodendrocytes.
“Too little is known about the mechanisms behind progressive MS, by which I mean the phase of the disease in which oligodendrocytes and neurons in the brain die without re-forming,” Karl Carlström, PhD, first author of the study, said in a press release.
Tecfidera (dimethyl fumarate, or DMF) is a therapy approved for the treatment of relapsing forms of MS. It has been suggested that its active ingredient — dimethyl fumarate — contributes to the maturation (differentiation) of oligodendrocytes by directly activating a pathway known as Nrf2, thus preventing myelin loss.
The team first confirmed that incubating OPCs isolated from neonatal rat brains with Tecfidera, along with a similar chemical called clemastine fumarate (Clem-F, sold as an allergy medicine under the name Tavegil) increased the production of Plp1, a protein essential in myelin.
Tecfidera and Clem-F also activated the Nrf2 pathway in oligodendrocytes, which triggered the production of a protein called glutathione S-transferase 4-alpha (Gsta4). Increased levels of Gsta4 were found in growing oligodendrocytes.
In contrast, blocking Gsta4 reduced the Plp1-inducing effects of Tecfidera and Clem-F. “Gsta4 thus acts downstream of DMF [Tecfidera] and Clem-F to promote [oligodendrocyte] differentiation,” the researchers wrote.
The role of Gsta4 was validated by showing that oligodendrocyte growth and Plp1 production was significantly enhanced in brain tissue of rats specially bred to overproduce the protein, by regulating the maturation from precursor cells to oligodendrocytes.
“In our study we identify a gene called Gsta4, which is especially important to the maturation process of oligodendrocytes,” said Carlström. “Interestingly, it seems some known and future MS drugs speed up this process in rats through this very gene.”
“Remove Gsta4 and they lose this effect,” he said.
Further analysis into the role of Gsta4 found that it reduced the activity of two signaling pathways associated with programmed cell death (apoptosis): Fas and Caspase-8 (Casp8). Casp8 is a protein located in the small cellular structures known as mitochondria — the cell’s powerhouse. Blocking Gsta4 in oligodendrocytes increased the levels of Casp8 in mitochondria.
Experiments to address whether Gsta4 contributes to myelin repair found that rats that overproduce Gsta4 were more efficient at remyelination compared to normal rats when demyelination was induced.
Finally, using a MS animal model — experimental autoimmune encephalomyelitis (EAE) model — researchers tested normal rats and rats over-expressing Gsta4. While the autoimmune response was similar in both rat strains, after disease onset, the Gsta4 over-producing rats showed a milder disease course, with reduced disease duration and disability scores compared to normal rats.
“Taken together, this set of experiments suggests that Gsta4 over-expression contributes to a lowering of mitochondrial stress and activation of Casp8, which in turn results in less extensive demyelination and/or improved remyelination, as well as ameliorated clinical symptoms,” the researchers concluded.
“Our results identify Gsta4 as an intrinsic regulator of [oligodendrocytes] differentiation, survival and remyelination, as well as a potential target for future reparative MS therapies,” they added.
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