STIMULATION OF OLIGODENDROGENESIS WITH THE SMALL MOLECULE WAY-316606 IN A MOUSE MODEL FOR PARKINSON’S DISEASE

Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and motor dysfunction. Emerging results define loss of oligodendrocyte as an early PD symptom to be targeted for early intervention by stimulating oligodendrogenesis. The small molecule WAY-316606 has been shown to activate the Wnt pathway and stimulate proliferation of oligodendrocytes in the subventricular zone (SVZ) of early postnatal mice by inhibiting SFRP signaling. In this study, we investigated the potential of the small molecule WAY to stimulate oligodendrogenesis in a PD mouse model.
Adult mice were administered MPTP to induce dopaminergic neuron loss and model PD-like pathology. WAY-316606 was administered intraperitoneally to control mice and MPTP-lesioned mice. Cell proliferation was assessed by administering BrdU in drinking water for 7 days. The SVZ was anatomically subdivided into dorsal, lateral, and medial SVZ (dSVZ, lSVZ, and mSVZ), and proliferating oligodendrocyte progenitor cells were quantified according to SVZ subregion localization.
Our results show that MPTP induced lesion increased late oligodendrocyte progenitor cells (OPCs) proliferation in the dSVZ only. In MPTP-lesioned mice, WAY-316606 selectively enhanced oligodendrocyte lineage cell proliferation in the lSVZ, whereas in control mice it preferentially promoted late OPC proliferation in the dSVZ. These findings reveal distinct, subregion-specific responses of adult SVZ progenitors to injury and pharmacological Wnt pathway activation. Evaluating the functional integration of these cells could reveal the therapeutic relevance of stimulating oligodendrogenesis for neurorepair in PD.