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Ifngr1 and Stat1 mediated canonical Ifn-? signaling drives nigrostriatal degeneration.

ABSTRACT: Brain expression of AAV-Ifn-? leads to reactive gliosis, nigrostriatal degeneration and midbrain calcification in wild type mice. This mouse model phenocopies idiopathic basal ganglia calcification which is associated with Parkinsonian symptoms. To understand how the nigro-striatal pathway is selectively vulnerable to Ifn-?, we determined if the phenotype is driven by canonical signaling intermediates, Ifngr1 and Stat1. Using focused bioinformatic analysis and rotarod testing, we show that neuroinflammation and motor abnormalities precede the appearance of midbrain neuropathologies in the brains of Ifn-? mouse model. To test whether canonical Ifn-? signaling is a key driver of progressive nigrostriatal degeneration, we overexpressed Ifn-? in the brains of Ifngr1-/- and Stat1-/- mice. Expression of Ifn-? in Ifngr1-/- mice did not result in any neuroinflammation, midbrain calcinosis or nigrostriatal degenerative pathology. Interestingly, in Stat1-/- mice, Ifn-? expression resulted in gliosis without recapitulating the neurodegenerative phenotype. Overall, our data shows that canonical Ifn-? signaling triggers midbrain calcinosis and nigrostriatal neurodegeneration, providing mechanistic insights into cytokine-driven selective neuronal vulnerability. Our study establishes the broader relevance of inflammatory signaling in neurodegenerative diseases and can potentially identify novel immunological targets for Parkinsonian syndromes.

SUBMITTER: Strickland MR

PROVIDER: S-EPMC5748010 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Ifngr1 and Stat1 mediated canonical Ifn-γ signaling drives nigrostriatal degeneration.

Strickland Michael R MR Koller Emily J EJ Deng Doris Z DZ Ceballos-Diaz Carolina C Golde Todd E TE Chakrabarty Paramita P

Neurobiology of disease 20171128

Brain expression of AAV-Ifn-γ leads to reactive gliosis, nigrostriatal degeneration and midbrain calcification in wild type mice. This mouse model phenocopies idiopathic basal ganglia calcification which is associated with Parkinsonian symptoms. To understand how the nigro-striatal pathway is selectively vulnerable to Ifn-γ, we determined if the phenotype is driven by canonical signaling intermediates, Ifngr1 and Stat1. Using focused bioinformatic analysis and rotarod testing, we show that neuro ...[more]

PMID: 29196213

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Project description:The classical model of cytokine signaling dominates our view of specific gene activation by cytokines such as the interferons (IFNs). The importance of the model extends beyond cytokines and applies to hormones such as growth hormone (GH) and insulin, and growth factors such as epidermal growth factor (EGF) and fibroblast growth factor (FGF). According to this model, ligand activates the cell via interaction with the extracellular domain of the receptor. This results in activation of receptor or receptor-associated tyrosine kinases, primarily of the Janus activated kinase (JAK) family, phosphorylation and dimerization of the signal transducer and activator of transcription (STAT) transcription factors, which dissociate from the receptor cytoplasmic domain and translocate to the nucleus. This view ascribes no further role to the ligand, JAK kinase, or receptor in either specific gene activation or the associated epigenetic events. The presence of dimeric STATs in the nucleus essentially explains it all. Our studies have resulted in the development of a non-canonical, more complex model of IFNγ signaling that is akin to that of steroid hormone (SH)/steroid receptor (SR) signaling. We have shown that ligand, receptor, activated JAKs, and STATs are associated with specific gene activation, where the receptor subunit IFNGR1 functions as a co-transcription factor and the JAKs are involved in associated epigenetic events. We found that the type I IFN system functions similarly. The fact that GH receptor, insulin receptor, EGF receptor, and FGF receptor undergo nuclear translocation upon ligand binding suggests that they may also function similarly. The SH/SR nature of type I and II IFN signaling provides insight into the specificity of signaling by members of cytokine families. The non-canonical model could also provide better understanding to more complex cytokine families such as those of IL-2 and IL-12, whose members often use the same JAKs and STATs, but also have different functions and properties.

Dataset Information

Ifngr1 and Stat1 mediated canonical Ifn-? signaling drives nigrostriatal degeneration.

Publications

Ifngr1 and Stat1 mediated canonical Ifn-γ signaling drives nigrostriatal degeneration.

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