title: Mortalin inhibition in experimental Parkinson's disease.
abstract: Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6-hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT-077, a rhodamine-123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham-operated, and 6-hydroxydopamine-denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6-hydroxydopamine-treated rats in comparison with sham-operated animals. MKT-077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT-077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease.
authors.affiliation: Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Chiasserini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.forename: Antonio
authors.initials: A
authors.lastname: de Iure
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.forename: Federica
authors.initials: F
authors.lastname: Susta
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Orvietani
authors.forename: Keizo
authors.initials: K
authors.lastname: Koya
authors.forename: Luciano
authors.initials: L
authors.lastname: Binaglia
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000977:Antiparasitic Agents / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000473:pathology; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D042967:Electron Transport Complex I / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D040901:Proteomics / Q000379:methods; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D000977:Antiparasitic Agents; D018840:HSP70 Heat-Shock Proteins; D011725:Pyridines; D013844:Thiazoles; C080352:mortalin; D016627:Oxidopamine; C097880:MKT 077; D042967:Electron Transport Complex I