Qian H, Kang X, Hu J, Zhang D, Liang Z, Meng F, Zhang X, Xue Y, Maimon R, Dowdy SF, Devaraj NK, Zhou Z, Mobley WC, Cleveland DW, Fu XD. Reversing a model of Parkinson’s disease with in situ converted nigral neurons. Nature, June 24, 2020

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  1. This is a very interesting study from the perspective of trans-differentiation of mature cells into other cell types.

    The data generated here depends heavily on the use of transgenic mice, introducing potential confounding factors such as promoter leakage. Cre-dependent animal models are very well-suited for developmental studies of cell lineage tracing, but are less appropriate for long-term studies in adult animals. Here the GFAP promoter will express high levels of Cre-recombinase in astrocytes and low levels in other cell types. Such low levels of Cre-recombinase activity over a period of months can lead to RFP labeling of mature neurons, and so there is a need for a robust reproduction of this data in non-transgenic mice.

    The Parkinson lesion in the mice needs to use a dose of 6OHDA that gives a clear and complete loss of dopaminergic neurons rather than partial lesions (at low 6-OHDA doses used in this study). An interpretation consistent with the author’s data is a confound of two mechanisms rather than direct trans-differentiation into authentic midbrain dopaminergic neurons: (1) blocked ptbp1 turns transduced astrocytes into growth factor producing neuron-like cells, which can protect and activate remaining host dopamine neurons from the partial lesion, and (2) blocked btbp1 promotes Cre leakage, labeling non-lesioned neurons with RFP. Should the ptbp1 inhibition in vivo lead to neuroprotective events, or be shown to create authentic midbrain neurons in models with complete loss of dopamine neurons—this would be a very interesting preliminary study for evaluating therapeutic relevance.

    View all comments by Ole Isacson

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