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Induced pluripotent stem cell-derived primary proprioceptive neurons as Friedreich ataxia cell model

Chiara Dionisi, Myriam Rai, Marine Chazalon, Serge N. Schiffmann, Massimo Pandolfo
doi: https://doi.org/10.1101/829358
Chiara Dionisi
Laboratory of Experimental Neurology, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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Myriam Rai
Laboratory of Experimental Neurology, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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Marine Chazalon
Laboratory of Neurophysiology, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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Serge N. Schiffmann
Laboratory of Neurophysiology, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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Massimo Pandolfo
Laboratory of Experimental Neurology, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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  • For correspondence: massimo.pandolfo@ulb.ac.be
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Abstract

Human induced pluripotent stem cells (iPSCs) are used to generate models of human diseases that recapitulate the pathogenic process as it occurs in affected cells. Many differentiated cell types can currently be obtained from iPSCs, but no validated protocol is yet available to specifically generate primary proprioceptive neurons. Proprioceptors are affected in a number of genetic and acquired diseases, including Friedreich ataxia (FRDA).

FRDA is a recessive neurodegenerative and systemic disease due to epigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at the FXN locus. The most characteristic early neuropathologic finding in FRDA is the loss of large primary proprioceptive neurons in the dorsal root ganglia (DRGs), with associated loss of large myelinated fibers in the dorsal roots and in the posterior columns of the spinal cord. Both a developmental deficit and progressive neurodegeneration are thought to underlie the loss of proprioceptors in FRDA, though the relative contribution of these two components is unclear. The basis of the high specific vulnerability of proprioceptors in FRDA is also unknown. In order to address these open questions about FRDA pathogenesis and at the same time develop a cell model that can be applied to other conditions primarily affecting proprioceptors, we set up a protocol to differentiate iPSCs into primary proprioceptive neurons. We modified the dual-SMAD inhibition/WNT activation protocol, previously used to generate nociceptor-enriched cultures of primary sensory neurons from iPSCs, to favor instead the generation of proprioceptors. We succeeded in substantially enriching iPSC-derived primary sensory neuron cultures in proprioceptors, largely exceeding the proportion normally represented by these cells in dorsal root ganglia. We also showed that almost pure populations of proprioceptors can be purified from these cultures by fluorescence-activated cell sorting. Finally, we demonstrated that iPSCs from a FRDA patient can generate normal appearing proprioceptors but have subtle differentiation deficits and more limited survival.

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Posted November 06, 2019.
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Induced pluripotent stem cell-derived primary proprioceptive neurons as Friedreich ataxia cell model
Chiara Dionisi, Myriam Rai, Marine Chazalon, Serge N. Schiffmann, Massimo Pandolfo
bioRxiv 829358; doi: https://doi.org/10.1101/829358
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Induced pluripotent stem cell-derived primary proprioceptive neurons as Friedreich ataxia cell model
Chiara Dionisi, Myriam Rai, Marine Chazalon, Serge N. Schiffmann, Massimo Pandolfo
bioRxiv 829358; doi: https://doi.org/10.1101/829358

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