Suppressing PRKG2 alleviates demyelination in neurological disorders

ABSTRACT: Demyelination is a common pathological feature of numerous neurodegenerative diseases, including multiple sclerosis (MS) and Huntington’s disease (HD). Previous studies have shown that the MyRF (Myelin Regulatory Factor)-containing complex initiates the transcription of myelin genes, whereas PRKG2 (cGMP-dependent protein kinase II) reduces MyRF phosphorylation, thereby inhibiting its transcriptional activity. However, the therapeutic potential of suppressing PRKG2 in demyelinating diseases remains unknown. In the present study, we found that the NO/cGMP/PKGs cascade, which activated PRKG2, was elevated in the serum of MS patients, in experimental autoimmune encephalomyelitis or cuprizone-induced MS mouse models, and in oligodendrocyte-specific HD mice. Knockdown of PRKG2 via CRISPR/Cas9 or antisense oligonucleotides (ASOs) efficiently alleviated demyelination in both MS and HD mouse models. Moreover, oral administration of the PRKG2 inhibitor Fasudil improved the expression of myelin-associated proteins and ameliorated motor dysfunction in HD mice. Mechanistically, we uncovered that PRKG2 suppression enhanced the binding of MyRF to promoter regions of myelin-associated transcripts. Collectively, our findings identify PRKG2 as a promising pharmacological target for alleviating demyelination in neurological disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE329788 | GEO | 2026/10/01

REPOSITORIES: GEO