👤 Kai Diederich

Demyelination of corticospinal tract neurons contributes to long-term disability after cortical stroke. Nonetheless, poststroke myelin loss has not been addressed as a therapeutic target, so far. We hypothesized that an antibody-mediated inhibition of the Nogo receptor-interacting protein (LINGO-1, leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein) may counteract myelin loss, enhance remyelination and axonal growth, and thus promote functional recovery following stroke. To verify this hypothesis, mice were subjected to photothrombotic stroke and received either an antibody against LINGO-1 (n = 19) or a control treatment (n = 18). Behavioral tests were performed to assess the effects of anti-LINGO-1 treatment on the functional recovery. Seven weeks after stroke, immunohistochemical analyses were performed to analyze the effect of anti-LINGO-1 treatment on myelination and axonal loss of corticospinal tract neurons, proliferation of oligodendrocytes and neurogenesis. Anti-LINGO-1 treatment resulted in significantly improved functional recovery (p < 0.0001, repeated measures analysis of variance), and increased neurogenesis in the hippocampus and subventricular zone of the ipsilateral hemisphere (p = 0.0094 and p = 0.032, t-test). Notably, we observed a significant increase in myelin (p = 0.0295, t-test), platelet-derived growth factor receptor α-positive oligodendrocyte precursor cells (p = 0.0356, t-test) and myelinating adenomatous polyposis coli-positive cells within the ipsilateral internal capsule of anti-LINGO-1-treated mice (p = 0.0021, t-test). In conclusion, we identified anti-LINGO-1 as the first neuroregenerative treatment that counteracts poststroke demyelination of corticospinal tract neurons, presumably by increased proliferation of myelin precursor cells, and thereby improves functional recovery. Most importantly, our study presents myelin loss as a novel therapeutic target following stroke. Show less

In the absence of ligands, the nuclear receptor PPARβ/δ recruits the NCOR and SMRT corepressors, which form complexes with HDAC3, to canonical target genes. Agonistic ligands cause dissociation of corepressors and enable enhanced transcription. Vice versa, synthetic inverse agonists augment corepressor recruitment and repression. Both basal repression of the target gene ANGPTL4 and reinforced repression elicited by inverse agonists are partially insensitive to HDAC inhibition. This raises the question how PPARβ/δ represses transcription mechanistically. We show that the PPARβ/δ inverse agonist PT-S264 impairs transcription initiation by decreasing recruitment of activating Mediator subunits, RNA polymerase II, and TFIIB, but not of TFIIA, to the ANGPTL4 promoter. Mass spectrometry identifies NCOR as the main PT-S264-dependent interactor of PPARβ/δ. Reconstitution of knockout cells with PPARβ/δ mutants deficient in basal repression results in diminished recruitment of NCOR, SMRT, and HDAC3 to PPAR target genes, while occupancy by RNA polymerase II is increased. PT-S264 restores binding of NCOR, SMRT, and HDAC3 to the mutants, resulting in reduced polymerase II occupancy. Our findings corroborate deacetylase-dependent and -independent repressive functions of HDAC3-containing complexes, which act in parallel to downregulate transcription. Show less