Remote control of induced dopaminergic neurons in parkinsonian rats

Maria Teresa Dell'Anno, Massimiliano Caiazzo, Damiana Leo, Elena Dvoretskova, Lucian Medrihan, Gaia Colasante, Serena Giannelli, Ilda Theka, Giovanni Russo, Liudmila Mus, Gianni Pezzoli, Raul R. Gainetdinov, Fabio Benfenati, Stefano Taverna, Alexander Dityatev, Vania Broccoli

Research output: Contribution to journalArticle

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Abstract

Direct lineage reprogramming through genetic-based strategies enables the conversion of differentiated somatic cells into functional neurons and distinct neuronal subtypes. Induced dopaminergic (iDA) neurons can be generated by direct conversion of skin fibroblasts; however, their in vivo phenotypic and functional properties remain incompletely understood, leaving their impact on Parkinson's disease (PD) cell therapy and modeling uncertain. Here, we determined that iDA neurons retain a transgene-independent stable phenotype in culture and in animal models. Furthermore, transplanted iDA neurons functionally integrated into host neuronal tissue, exhibiting electrically excitable membranes, synaptic currents, dopamine release, and substantial reduction of motor symptoms in a PD animal model. Neuronal cell replacement approaches will benefit from a system that allows the activity of transplanted neurons to be controlled remotely and enables modulation depending on the physiological needs of the recipient; therefore, we adapted a DREADD (designer receptor exclusively activated by designer drug) technology for remote and real-time control of grafted iDA neuronal activity in living animals. Remote DREADD-dependent iDA neuron activation markedly enhanced the beneficial effects in transplanted PD animals. These data suggest that iDA neurons have therapeutic potential as a cell replacement approach for PD and highlight the applicability of pharmacogenetics for enhancing cellular signaling in reprogrammed cell-based approaches.

Original languageEnglish
Pages (from-to)3215-3229
Number of pages15
JournalJournal of Clinical Investigation
Volume124
Issue number7
DOIs
Publication statusPublished - Jul 1 2014

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Dopaminergic Neurons
Parkinson Disease
Designer Drugs
Animal Models
Neurons
Synaptic Membranes
Pharmacogenetics
Cell- and Tissue-Based Therapy
Transgenes
Dopamine
Fibroblasts
Technology
Phenotype
Skin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dell'Anno, M. T., Caiazzo, M., Leo, D., Dvoretskova, E., Medrihan, L., Colasante, G., ... Broccoli, V. (2014). Remote control of induced dopaminergic neurons in parkinsonian rats. Journal of Clinical Investigation, 124(7), 3215-3229. https://doi.org/10.1172/JCI74664

Remote control of induced dopaminergic neurons in parkinsonian rats. / Dell'Anno, Maria Teresa; Caiazzo, Massimiliano; Leo, Damiana; Dvoretskova, Elena; Medrihan, Lucian; Colasante, Gaia; Giannelli, Serena; Theka, Ilda; Russo, Giovanni; Mus, Liudmila; Pezzoli, Gianni; Gainetdinov, Raul R.; Benfenati, Fabio; Taverna, Stefano; Dityatev, Alexander; Broccoli, Vania.

In: Journal of Clinical Investigation, Vol. 124, No. 7, 01.07.2014, p. 3215-3229.

Research output: Contribution to journalArticle

Dell'Anno, MT, Caiazzo, M, Leo, D, Dvoretskova, E, Medrihan, L, Colasante, G, Giannelli, S, Theka, I, Russo, G, Mus, L, Pezzoli, G, Gainetdinov, RR, Benfenati, F, Taverna, S, Dityatev, A & Broccoli, V 2014, 'Remote control of induced dopaminergic neurons in parkinsonian rats', Journal of Clinical Investigation, vol. 124, no. 7, pp. 3215-3229. https://doi.org/10.1172/JCI74664
Dell'Anno MT, Caiazzo M, Leo D, Dvoretskova E, Medrihan L, Colasante G et al. Remote control of induced dopaminergic neurons in parkinsonian rats. Journal of Clinical Investigation. 2014 Jul 1;124(7):3215-3229. https://doi.org/10.1172/JCI74664
Dell'Anno, Maria Teresa ; Caiazzo, Massimiliano ; Leo, Damiana ; Dvoretskova, Elena ; Medrihan, Lucian ; Colasante, Gaia ; Giannelli, Serena ; Theka, Ilda ; Russo, Giovanni ; Mus, Liudmila ; Pezzoli, Gianni ; Gainetdinov, Raul R. ; Benfenati, Fabio ; Taverna, Stefano ; Dityatev, Alexander ; Broccoli, Vania. / Remote control of induced dopaminergic neurons in parkinsonian rats. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 7. pp. 3215-3229.
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