Suppression of 6-pyruvoyl-tetrahydropterin synthase promotes remyelination in multiple sclerosis

Background: Multiple sclerosis (MS) is a CNS autoimmune disease that is characterized by demyelination, neuroinflammation, and neuronal loss. Although current chemotherapies and immunotherapies for MS efficiently mitigate disease activity and relief clinical symptoms, neuroprotection targeting axon/neurons remains therapeutically challenging. Accumulating evidence has suggested that poor oligodendrocyte precursor cell (OPC) proliferation and subsequent migration/differentiation significantly impedes remyelination during MS. However, the molecular mechanisms underlying OPCs dysfunction during MS remain elusive. Methods: Re-analysis of single cell sequencing data from human and mouse oligodendrocyte lineage cells (OLCs), along with staining results from brain sections of MS patients, was conducted to investigate the role of 6-pyruvoyl-tetrahydropterin synthase (PTS) in determining oligodendrocyte fate. To assess PTS function in MS, conditional knockout mice targeting OLCs were employed. Transcriptomic analyses further illuminated the molecular mechanisms through which PTS influences the disease process. Results: PTS in OPCs is a suppressor of OPC proliferation that contributes to demyelination in MS. We found that PTS expression in OPCs was aberrantly increased in patients with MS. Mice lacking Pts specifically in OPCs displayed ameliorated experimental autoimmune encephalitis (EAE) severity, a mouse model of MS, which were accompanied by attenuated demyelination. Moreover, selective suppression of Pts in OPCs facilitated OPC proliferation and remyelination during EAE. Mechanistically, the knockdown of Pts activated the cholesterol biosynthesis pathway leading to enhanced OPC proliferation. Conclusions: Our findings suggest that PTS is a negative regulator of OPC proliferation, and its disinhibition could offer a potential therapeutic target for MS.