title: The peptidyl-prolyl isomerase Pin1 up-regulation and proapoptotic function in dopaminergic neurons: relevance to the pathogenesis of Parkinson disease.
abstract: Parkinson disease (PD) is a chronic neurodegenerative disease characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra. The pathophysiological mechanisms underlying PD remain unclear. Pin1, a major peptidyl-prolyl isomerase, has recently been associated with certain diseases. Notably, Ryo et al. (Ryo, A., Togo, T., Nakai, T., Hirai, A., Nishi, M., Yamaguchi, A., Suzuki, K., Hirayasu, Y., Kobayashi, H., Perrem, K., Liou, Y. C., and Aoki, I. (2006) J. Biol. Chem. 281, 4117-4125) implicated Pin1 in PD pathology. Therefore, we sought to systematically characterize the role of Pin1 in PD using cell culture and animal models. To our surprise we observed a dramatic up-regulation of Pin1 mRNA and protein levels in dopaminergic MN9D neuronal cells treated with the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP(+)) as well as in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Notably, a marked expression of Pin1 was also observed in the substantia nigra of human PD brains along with a high co-localization of Pin1 within dopaminergic neurons. In functional studies, siRNA-mediated knockdown of Pin1 almost completely prevented MPP(+)-induced caspase-3 activation and DNA fragmentation, indicating that Pin1 plays a proapoptotic role. Interestingly, multiple pharmacological Pin1 inhibitors, including juglone, attenuated MPP(+)-induced Pin1 up-regulation, α-synuclein aggregation, caspase-3 activation, and cell death. Furthermore, juglone treatment in the MPTP mouse model of PD suppressed Pin1 levels and improved locomotor deficits, dopamine depletion, and nigral dopaminergic neuronal loss. Collectively, our findings demonstrate for the first time that Pin1 is up-regulated in PD and has a pathophysiological role in the nigrostriatal dopaminergic system and suggest that modulation of Pin1 levels may be a useful translational therapeutic strategy in PD.
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Anamitra
authors.initials: A
authors.lastname: Ghosh
authors.forename: Hariharan
authors.initials: H
authors.lastname: Saminathan
authors.forename: Arthi
authors.initials: A
authors.lastname: Kanthasamy
authors.forename: Vellareddy
authors.initials: V
authors.lastname: Anantharam
authors.forename: Huajun
authors.initials: H
authors.lastname: Jin
authors.forename: Gautam
authors.initials: G
authors.lastname: Sondarva
authors.forename: Dilshan S
authors.initials: DS
authors.lastname: Harischandra
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Qian
authors.forename: Ajay
authors.initials: A
authors.lastname: Rana
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012194:RNA-Directed DNA Polymerase; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D012194:RNA-Directed DNA Polymerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D015655:1-Methyl-4-phenylpyridinium; C005134:juglone
keywords: Caspase-3; Dopamine; Juglone; MPTP; Neurobiology; Neurodegenerative Diseases; Neuroprotection; Parkinson Disease; Pin1