PT109B Rapidly Converts Astrocytes to Dopaminergic Neurons and Alleviates Parkinson's Disease in Mice.

Reprogramming astrocytes into neurons using chemical small molecules has emerged as a promising therapeutic strategy for Parkinson's disease (PD). Here, we have identified PT109B, a novel multi-kinase inhibitor, as a potent agent that induces the direct reprogramming of astrocytes into functional induced dopaminergic neurons (iDANs) beginning with a remarkably short 6-hour window. Within just half a month, PT109B facilitated the maturation of iDANs, characterized by synaptic structures, electrophysiological properties, sustained dopamine release, and long-term viability (for over 3 months). Mechanistically, PT109B drove this conversion through cell cycle arrest, astrocytic activation, and upregulation of key basic Helix-Loop-Helix (b-HLH) transcription factors, including NeuroD1, Nurr1, Ngn2, and Ascl1. Importantly, oral administration of PT109B in a 6-OHDA-induced PD mouse model exhibited significant therapeutic efficacy by reprogramming astrocytes to functional neurons in the striatum, leading to improved motor functions. These findings suggest PT109B as a promising therapeutic candidate for PD. Overall design: RNA-seq of primary rat midbrain astrocytes at 1.5, 3, and 6 hours post-PT109B treatment