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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.

SUBMITTER: Torii S

PROVIDER: S-EPMC4981001 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Involvement of inhibitory PAS domain protein in neuronal cell death in Parkinson's disease.

Torii S S Kasai S S Suzuki A A Todoroki Y Y Yokozawa K K Yasumoto K-I KI Seike N N Kiyonari H H Mukumoto Y Y Kakita A A Sogawa K K

Cell death discovery 20150817

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 h ...[more]

PMID: 27551449

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Project description:In mammals, circadian rhythms are essential for coordinating the timing of various metabolic processes. The Clock gene regulates diurnal plasma triglyceride fluctuation through nuclear receptor small heterodimer partner (Shp; Nr0b2). Given that SHP is a critical regulator of metabolism in the liver, it is unknown whether SHP is necessary to coordinate metabolism and circadian rhythms. Shp(+/+) and Shp(-/-) mice on a C57BL/6 background (n = 3-5/group) were fed a standard chow diet and water ad libitum. Serum and livers were collected at zeitgeber time 2, 6, 10, 14, 18, and 22. In vivo and in vitro assays included RNA sequencing, quantitative polymerase chain reaction, very-low-density lipoprotein production, adenovirus overexpression and small interfering RNA knockdown, serum parameters, circadian locomotor activity, Oil Red O staining, transient transfection, luciferase reporter assay, chromatin immunoprecipitation assay, gel-shift assay, coimmunoprecipitation, and western blottings. Shp deficiency had a robust global impact on major liver metabolic genes. Several components of the liver clock, including peroxisome proliferator-activated receptor-?, coactivator 1 (Pgc-1?), neuronal PAS domain-containing protein 2 (Npas2), and retinoic acid-related orphan receptor (Ror)?/? were sharply induced in Shp(-/-) liver. At the molecular level, SHP inhibited Npas2 gene transcription and promoter activity through interaction with Ror? to repress Ror? transactivation and by interacting with Rev-erb? to enhance its inhibition of Ror? activity. Conversely, Npas2 controlled the circadian rhythm of Shp expression by binding rhythmically to the Shp promoter, which was enhanced by nicotinamide adenine dinucleotide, but not nicotinamide adenine dinucleotide phosphate. Phenotypically, Npas2 deficiency induced severe steatosis in Shp(-/-) mice, which was attributed to the dysregulation of lipoprotein metabolism.Shp and Npas2 crosstalk is essential to maintain hepatic lipid homeostasis.

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Involvement of inhibitory PAS domain protein in neuronal cell death in Parkinson's disease.

Publications

Involvement of inhibitory PAS domain protein in neuronal cell death in Parkinson's disease.

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