Ptbp1 deletion does not induce astrocyte-to-neuron conversion

T Hoang, DW Kim, H Appel, M Ozawa, S Zheng, J Kim… - Nature, 2023 - nature.com
Nature, 2023nature.com
Although in vivo reprogramming of astrocytes into neurons holds promise for treating
neurodegenerative disorders, protocols to achieve it are complex and inefficient. A recent
study reported that knockdown of Ptbp1 in the cortex, striatum and substantia nigra of the
midbrain efficiently reprogrammed astrocytes into functional neurons that rescued motor
defects in a mouse model of Parkinson's disease 1, but it did not convincingly demonstrate
that astrocyte-to-neuron conversion had actually occurred. Using genetic disruption of …
Although in vivo reprogramming of astrocytes into neurons holds promise for treating neurodegenerative disorders, protocols to achieve it are complex and inefficient. A recent study reported that knockdown of Ptbp1 in the cortex, striatum and substantia nigra of the midbrain efficiently reprogrammed astrocytes into functional neurons that rescued motor defects in a mouse model of Parkinson’s disease 1, but it did not convincingly demonstrate that astrocyte-to-neuron conversion had actually occurred. Using genetic disruption of Ptbp1in combination with cell-lineage analysis, we observe no astrocyte-to-neuron conversion or substantial changes in gene expression in Ptbp1-deficient astrocytes. We conclude that the results of astrocyte-to-neuron conversion in the previous study 1 most likely reflect leaky neuronal expression of the Gfapcre mouse lines used to label astrocytes, and more-rigorous experimental methods must be used to support their observations of glial reprogramming in vivo.
Observations by Qian et al. 1 that Ptbp1knockdown induced astrocyteto-neuron conversion in vivo lacked several essential controls. A reduction in Ptbp1 expression in astrocytes in vivo was not shown; lineage relationships between astrocytes and neurons were inferred using GFAP minipromoter constructs, which can show leaky neuronal expression 2–5; and direct evidence for glia-to-neuron conversion using genetic lineage analysis and/or single-cell RNA-sequencing (scRNA-seq) analysis was lacking. Here we conduct a genetic lineage and scRNA-seq analysis of mature astrocytes carrying heterozygous or homozygous mutants
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