title: Involvement of inhibitory PAS domain protein in neuronal cell death in Parkinson's disease.
abstract: Inhibitory PAS domain protein (IPAS), a repressor of hypoxia-inducible factor-dependent transcription under hypoxia, was found to exert pro-apoptotic activity in oxidative stress-induced cell death. However, physiological and pathological processes associated with this activity are not known. Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. Activation of the PINK1-Parkin pathway attenuated IPAS-dependent apoptosis. IPAS was markedly induced in the midbrain following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and IPAS-deficient mice showed resistance to MPTP-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). A significant increase in IPAS expression was found in SNpc neurons in patients with sporadic PD. These results indicate a mechanism of neurodegeneration in PD.
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University , Sendai, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Torii
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University , Sendai, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kasai
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University , Sendai, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University , Sendai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Todoroki
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University , Sendai, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yokozawa
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University , Sendai, Japan.
authors.forename: K-I
authors.initials: KI
authors.lastname: Yasumoto
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata , Niigata, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Seike
authors.affiliation: Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan; Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kiyonari
authors.affiliation: Genetic Engineering Team, RIKEN Center for Life Science Technologies , Kobe, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Mukumoto
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata , Niigata, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University , Sendai, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sogawa