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

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE292869 | GEO | 2026/01/01

REPOSITORIES: GEO

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