TY - JOUR
T1 - Interferon downstream signaling is activated early in pre-symptomatic Niemann-Pick disease type C
AU - Dong Kyu Shin, Samuel
AU - Shin, Alexandra
AU - Mayagoitia, Karina
AU - Wilson, Christopher G.
AU - Bellinger, Denise L.
AU - Soriano, Salvador
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/7/27
Y1 - 2019/7/27
N2 - 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.
AB - 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.
KW - Gene expression
KW - Neurodegeneration
KW - Neuroinflammation
KW - Niemann-Pick disease type C
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U2 - 10.1016/j.neulet.2019.05.005
DO - 10.1016/j.neulet.2019.05.005
M3 - Article
C2 - 31067492
SN - 0304-3940
VL - 706
SP - 43
EP - 50
JO - Neuroscience Letters
JF - Neuroscience Letters
ER -