Therapeutic Reversal of Chemically Induced Parkinson Disease by Converting Astrocytes into Nigral Neurons

SUMMARY Parkinson disease is characterized by loss of dopamine neurons in the substantia nigra. As with other neurodegenerative diseases, no disease-modifying treatments exist. While most treatment objectives aim to prevent neuronal loss or protect vulnerable neuronal circuits, an important alternative is to replace lost neurons to reconstruct disrupted circuits. Herein we report an efficient single-step conversion of isolated mouse and human astrocytes into functional neurons by depleting the RNA binding protein PTB. Applying this approach to mice with a chemically induced Parkinson’s phenotype, we provide evidence that disease manifestations can be potently reversed through converting astrocytes into new substantia nigral neurons, effectively restoring dopamine levels via reestablishing the nigrostriatal dopamine pathway. We further demonstrate similar disease reversal with a therapeutically feasible approach using antisense oligonucleotides to transiently suppress PTB. These findings identify a generalizable therapeutic strategy for treating neurodegenerative disorders through replacing lost neurons in the brain.