LAUSR

Contemporary management of Parkinson’s disease is directed at symptom control. To date, there are no disease-modifying therapies. Efforts at preventing or restoring neuronal loss and protecting degenerating circuits have been disappointing. Early efforts at cell replacement therapy used fetal midbrain tissue as a source of dopamine neurons for transplantation. Although transplants survived and fiber outgrowth could be detected, these studies resulted in only modest clinical benefit in younger patients in the short term. Furthermore, the use of fetal cells has been fraught with ethical, practical, and clinical difficulties that have led to the search for alternative stem cell sources. Reprogramming of fibroblasts and subsequently astrocytes to dopaminergic neurons in vitro was first reported in 2011. Subsequently, it was shown that mouse astroglia could be reprogrammed in situ into induced dopamine neurons that were excitable and able to correct some aspects of motor behavior in live mice. Thus far, however, reprogrammed striatal astrocytes have not been shown to reconstruct nigrostriatal circuitry. The RNA binding protein PTB and its neuronal analogue nPTB are sequentially downregulated during neurogenesis. Depleting PTB might reprogram astrocytes into functioning dopaminergic neurons that could innervate and repopulate endogenous neural circuits. Qian et al. describe the successful one-step conversion of isolated mouse and human astrocytes to functional neurons by depletion of PTB in vitro. They further describe astrocyteto-neuron conversion in the mouse midbrain, which provided functional dopaminergic axons to reconstruct the nigrostriatal circuit. In the 6-hydroxydopamine (6-OHDA) mouse model, neuronal cell bodies in the substantia nigra and their axonal projections were reduced by 90%. Using an adeno-associated virus expressing a small hairpin RNA against ptbp1 (AAV-shPTB) restored the neuronal population and fiber density to approximately one-third of the initial number. Striatal dopamine levels increased from about 25% of normal levels to approximately 65% of uninjured levels in the treated mice. Furthermore, 6-OHDA-treated mice restored motor function to nearly wild-type levels within 3 months. Applying the same conversion technique in the cortex and striatum resulted in an overall similar conversion efficiency; however, dopaminergic neurons were detected mainly in the midbrain. Their results suggest that this regional specificity is caused by midbrain astrocytes’ higher basal level of expression of dopaminergic neurons transcription factors, as well as the local microenvironment contribution.This new technique therefore has the potential not only to restore dopamine levels in the striatum but also to restore functionally normal circuitry. There are still hurdles to overcome, including theoretical constructional weakening caused by local astrocyte depletion, which may harm the blood-brain barrier, supply of nutrients, and neuronal synchrony, as well as potential side effects caused by mistargeted vulnerable neurons that may hamper other neural circuits. Next steps include improving reprogramming efficiency, demonstrating the approach on human adult striatal astrocytes, developing systems to selectively target human striatal astrocytes in vivo, and ensuring safety and efficacy in humans.