title: Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson's disease.
abstract: Recent evidence suggests an early involvement of dopaminergic (DA) processes and terminals in Parkinson's disease (PD). The arborization of neurons depends on the actin cytoskeleton, which in turn is regulated by small GTPases of the Rho family, encompassing Rho, Rac and Cdc42 subfamilies. Indeed, some reports point to a role for Rac and Cdc42 signaling in the pathophysiology of inherited parkinsonisms. We thus investigated the potential therapeutic effect of the modulation of cerebral Rho GTPases in PD. Cytotoxic necrotizing factor 1 (CNF1), a 114 kDa protein toxin produced by Escherichia coli, permanently activates RhoA, Rac1 and Cdc42 in intact cells. We report that the modulation of Rho GTPases by CNF1 results in hypertrophy of DA cell processes of cultured substantia nigra neurons, including increase in length, branching and varicosity. In vivo, the treatment corrects long-standing motor and biochemical asymmetries and restores degenerated nigrostriatal DA tissue after 6-hydroxydopamine lesion. We conclude that the pharmacological modulation of Rho GTPases shows neurorestorative potential and represents a promising avenue in the treatment PD. The study also suggests that naturally occurring molecules acting on Rho GTPase signaling, such as some bacterial protein toxins, might play a role in the development of PD.
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Roma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Musilli
authors.affiliation: Institute of Cellular Biology and Neurobiology, Consiglio Nazionale delle Ricerche, Via del Fosso di Fiorano, 64, 00143, Roma, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ciotti
authors.affiliation: Department of Experimental Medicine and Surgery, University of "Tor Vergata", Viale Oxford, 81, 00133, Roma, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pieri
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Roma, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Martino
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Roma, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Borrelli
authors.affiliation: Department of Experimental Medicine and Surgery, University of "Tor Vergata", Viale Oxford, 81, 00133, Roma, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dinallo
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Roma, Italy. Electronic address: giovanni.diana@iss.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Diana
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D029968:Escherichia coli Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D016896:Treatment Outcome; D020741:rho GTP-Binding Proteins / Q000819:agonists* / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; C060296:cytotoxic necrotizing factor type 1; D020741:rho GTP-Binding Proteins
keywords: 6-Hydroxydopamine; Bacteria; Bacterial toxins; Cdc42; Neurodegeneration; Rac; Rho