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

• Published in: Genes Vol. 15; no. 1; p. 101
• Main Authors: Tolan, Andrew J, Sanchez, Kayla L, Shin, Samuel D, White, Jacob B, Currais, Antonio, Soriano-Castell, David, Wilson, Christopher G, Maher, Pamela, Soriano, Salvador
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.01.2024
• Subjects: Age; Analysis; Biological response modifiers; Brain; Cerebellum; Cerebral cortex; Cholesterol; Cytokines; Development and progression; Endosomes; Gene expression; Genes; Genetic aspects; Genomes; Genomics; Interferon; Lymphocytes; Lysosomes; Neurodegeneration; Niemann-Pick disease; Npc1 protein; Ontology; Oxidative stress; Pick's disease; Software; Transcriptomes; Transcriptomics; United States > US; neurodegeneration; Niemann–Pick disease type C; interferon signaling
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes15010101

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the or 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 mice. Here, we carried out a comparative transcriptomic analysis of cerebral cortices and cerebella of pre-symptomatic 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.