Interferon downstream signaling is activated early in pre-symptomatic Niemann-Pick disease type C
| Autor: | Denise L. Bellinger, Alexandra Shin, Salvador Soriano, Karina Mayagoitia, Christopher G. Wilson, Samuel Dong Kyu Shin |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Prodromal Symptoms CCL3 CCL5 Mice 03 medical and health sciences 0302 clinical medicine Niemann-Pick C1 Protein Interferon Cerebellum medicine Animals CXCL10 Neuroinflammation Mice Knockout business.industry Gene Expression Profiling General Neuroscience Neurodegeneration Intracellular Signaling Peptides and Proteins Niemann-Pick Disease Type C medicine.disease stomatognathic diseases 030104 developmental biology Cytokine Cancer research Cytokines CXCL9 Interferons business 030217 neurology & neurosurgery Genome-Wide Association Study Signal Transduction medicine.drug |
| Zdroj: | Neuroscience Letters. 706:43-50 |
| ISSN: | 0304-3940 |
| DOI: | 10.1016/j.neulet.2019.05.005 |
| Popis: | Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition with no FDA-approved therapy. Previous studies demonstrated that neuroinflammation is an early pathologic event and a disease modifier of NPC, affecting symptomatic onset and overall lifespan. Therefore, NPC-specific anti-inflammatory therapy may result in clinical benefit. However, to date, the initial trigger of the inflammatory onset and the mechanism driving the sustained chronic neuroinflammation remain unknown. In this study, we utilized a genome-wide transcriptome analysis to identify the key pathways involved in early NPC. Our results showed that an atypical pattern of interferon downstream signaling that involves both IFN-γ- and IFN-α-responsive genes is activated in pre-symptomatic Npc1-/- cerebella. Functional analysis of the differentially expressed genes highlighted microglial activation, anti-viral response, and T-lymphocyte activation and chemotaxis pathways. Multiplex protein analysis confirmed that a potent IFN-γ-responsive cytokine, IP-10/CXCL10 was significantly upregulated in the pre-symptomatic stage and further exacerbated in the terminal stage. In addition, several IFN-γ-responsive cytokines were elevated in the terminal stage Npc1-/- cerebella, including MIG/CXCL9, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, M-CSF, and IL-1α. Together, our results describe a novel activation pattern of interferon downstream signaling in pre-symptomatic NPC, as well as key inflammatory mediators that could serve as potential targets for NPC-specific anti-inflammatory therapy. |
| Databáze: | OpenAIRE |
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