Reversing a model of Parkinson’s disease with in situ converted nigral neurons

Abstract

SUMMARY Parkinson disease is characterized by loss of dopamine neurons in the substantia nigra 1 . Similar to other major neurodegenerative disorders, no disease-modifying treatment exists. While most treatment strategies aim to prevent neuronal loss or protect vulnerable neuronal circuits, a potential alternative is to replace lost neurons to reconstruct disrupted circuits 2 . 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 the mouse brain, we demonstrate progressive conversion of astrocytes into new neurons that can innervate into endogenous neural circuits. Astrocytes in different brain regions are found to convert into different neuronal subtypes. Using a chemically induced model of Parkinson’s disease, we show conversion of midbrain astrocytes into dopaminergic neurons whose axons reconstruct the nigro-striatal circuit. Significantly, re-innervation of striatum is accompanied by restoration of dopamine levels and rescue of motor deficits. Similar disease phenotype reversal is also accomplished by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB. These findings identify a potentially powerful and clinically feasible new approach to treating neurodegeneration by replacing lost neurons.

Induced in vivo transdifferentiation of vertebrate muscle into early endoderm-like cells

“…The low frequency and spatial propensity of induced ptf1a:GFP expression led us to posit that only certain iEndo cells with optimal intrinsic (intracellular) and extrinsic (extracellular/microenvironment) conditions will proceed toward a speci c endoderm lineage pathway such as liver, intestine, or pancreas. This in uence by the microenvironment on pancreas lineage commitment is analogous to the regional speci city observed for induced in vivo transdifferentiation of astrocytes into dopaminergic neurons 20 . The skeletal muscle microenvironment has previously been demonstrated to be permissive for human pancreas cell differentiation and function [21][22][23][24] .…”

Rapid and efficientin vivoastrocyte-to-neuron conversion with regional identity and connectivity?

“…With the advancements of cell fate reprogramming, in vivo conversion of resident glial cells to functional new neurons emerges as a promising strategy for neural regeneration (Barker et al, 2018;Chen et al, 2015;Li and Chen, 2016;Pereira et al, 2019;Smith and Zhang, 2015;Tai et al, 2020;Torper and Gotz, 2017;Wang and Zhang, 2018). This is largely accomplished by the ectopic expression of a single or a combination of fate-determining factors or through knockdown of a single gene (Grande et al, 2013;Guo et al, 2014;Liu et al, 2015;Niu et al, 2013;Qian et al, 2020;Torper et al, 2015;Zhou et al, 2020). Resident glial cells are ideal cell sources for fateconversions, since they become reactive and can proliferate to replenish themselves in response to injury or neurodegeneration.…”

MiR-124 and small molecules synergistically regulate the direct generation of neuronal cells from rat cortical reactive astrocytes

“…Repressing the RNA-binding protein, PTBP1 has recently been reported to mediate astrocyte-todopaminergic neuron conversion in a Parkinson's disease (PD) mouse model [25,26]. We suspect that as one of the targets of miR-124 [27], Ptbp1 of RAs may be targeted by miR-124 to promote their neuronal differentiation.…”