title: Remote control of induced dopaminergic neurons in parkinsonian rats.
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.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Dell'Anno
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Caiazzo
authors.forename: Damiana
authors.initials: D
authors.lastname: Leo
authors.forename: Elena
authors.initials: E
authors.lastname: Dvoretskova
authors.forename: Lucian
authors.initials: L
authors.lastname: Medrihan
authors.forename: Gaia
authors.initials: G
authors.lastname: Colasante
authors.forename: Serena
authors.initials: S
authors.lastname: Giannelli
authors.forename: Ilda
authors.initials: I
authors.lastname: Theka
authors.forename: Giovanni
authors.initials: G
authors.lastname: Russo
authors.forename: Liudmila
authors.initials: L
authors.lastname: Mus
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.forename: Stefano
authors.initials: S
authors.lastname: Taverna
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
authors.forename: Vania
authors.initials: V
authors.lastname: Broccoli
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D054338:Cell Transdifferentiation / Q000235:genetics; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D015198:Designer Drugs; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology / Q000637:transplantation*; D055724:Electrophysiological Phenomena; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D055647:Rats, Transgenic
chemical_list: D015198:Designer Drugs; D003024:Clozapine; C079149:clozapine N-oxide; D004298:Dopamine