Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann–Pick Disease Type C
Niemann–Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the <i>NPC1</i> or <i>NPC2</i> genes that encode the NPC1 and NPC2 proteins, respectively, which are believed to be responsible for cholesterol efflux from late-endosomes/l...
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MDPI AG
2024-01-01
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| Online Access: | https://www.mdpi.com/2073-4425/15/1/101 |
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| author | Andrew J. Tolan Kayla L. Sanchez Samuel D. Shin Jacob B. White Antonio Currais David Soriano-Castell Christopher G. Wilson Pamela Maher Salvador Soriano |
| author_facet | Andrew J. Tolan Kayla L. Sanchez Samuel D. Shin Jacob B. White Antonio Currais David Soriano-Castell Christopher G. Wilson Pamela Maher Salvador Soriano |
| author_sort | Andrew J. Tolan |
| collection | DOAJ |
| description | Niemann–Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the <i>NPC1</i> or <i>NPC2</i> genes that encode the NPC1 and NPC2 proteins, respectively, which are believed to be responsible for cholesterol efflux from late-endosomes/lysosomes. The pathogenic mechanisms that lead to neurodegeneration in NPC are not well understood. There are, however, well-defined spatiotemporal patterns of neurodegeneration that may provide insight into the pathogenic process. For example, the cerebellum is severely affected from early disease stages, compared with cerebral regions, which remain relatively spared until later stages. Using a genome-wide transcriptome analysis, we have recently identified an aberrant pattern of interferon activation in the cerebella of pre-symptomatic <i>Npc1<sup>−/−</sup></i> mice. Here, we carried out a comparative transcriptomic analysis of cerebral cortices and cerebella of pre-symptomatic <i>Npc1<sup>−/−</sup></i> mice and age-matched controls to identify differences that may help explain the pathological progression within the NPC brain. We report lower cerebral expression of genes within interferon signaling pathways, and significant differences in the regulation of oxidative stress, compared with the cerebellum. Our findings suggest that a delayed onset of interferon signaling, possibly linked to lower oxidative stress, may account for the slower onset of cerebral cortical pathology in the disease. |
| first_indexed | 2024-03-08T10:52:22Z |
| format | Article |
| id | doaj.art-7e0a84555adb4e77af0ac94c1bb14dd9 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-08T10:52:22Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-7e0a84555adb4e77af0ac94c1bb14dd92024-01-26T16:43:24ZengMDPI AGGenes2073-44252024-01-0115110110.3390/genes15010101Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann–Pick Disease Type CAndrew J. Tolan0Kayla L. Sanchez1Samuel D. Shin2Jacob B. White3Antonio Currais4David Soriano-Castell5Christopher G. Wilson6Pamela Maher7Salvador Soriano8Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USADepartment of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USADepartment of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USADepartment of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USAThe Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USAThe Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USALawrence D. Longo Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USAThe Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USADepartment of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USANiemann–Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the <i>NPC1</i> or <i>NPC2</i> genes that encode the NPC1 and NPC2 proteins, respectively, which are believed to be responsible for cholesterol efflux from late-endosomes/lysosomes. The pathogenic mechanisms that lead to neurodegeneration in NPC are not well understood. There are, however, well-defined spatiotemporal patterns of neurodegeneration that may provide insight into the pathogenic process. For example, the cerebellum is severely affected from early disease stages, compared with cerebral regions, which remain relatively spared until later stages. Using a genome-wide transcriptome analysis, we have recently identified an aberrant pattern of interferon activation in the cerebella of pre-symptomatic <i>Npc1<sup>−/−</sup></i> mice. Here, we carried out a comparative transcriptomic analysis of cerebral cortices and cerebella of pre-symptomatic <i>Npc1<sup>−/−</sup></i> mice and age-matched controls to identify differences that may help explain the pathological progression within the NPC brain. We report lower cerebral expression of genes within interferon signaling pathways, and significant differences in the regulation of oxidative stress, compared with the cerebellum. Our findings suggest that a delayed onset of interferon signaling, possibly linked to lower oxidative stress, may account for the slower onset of cerebral cortical pathology in the disease.https://www.mdpi.com/2073-4425/15/1/101Niemann–Pick disease type Cneurodegenerationinterferon signaling |
| spellingShingle | Andrew J. Tolan Kayla L. Sanchez Samuel D. Shin Jacob B. White Antonio Currais David Soriano-Castell Christopher G. Wilson Pamela Maher Salvador Soriano Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann–Pick Disease Type C Genes Niemann–Pick disease type C neurodegeneration interferon signaling |
| title | Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann–Pick Disease Type C |
| title_full | Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann–Pick Disease Type C |
| title_fullStr | Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann–Pick Disease Type C |
| title_full_unstemmed | Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann–Pick Disease Type C |
| title_short | Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann–Pick Disease Type C |
| title_sort | differential interferon signaling regulation and oxidative stress responses in the cerebral cortex and cerebellum could account for the spatiotemporal pattern of neurodegeneration in niemann pick disease type c |
| topic | Niemann–Pick disease type C neurodegeneration interferon signaling |
| url | https://www.mdpi.com/2073-4425/15/1/101 |
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