Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 15, Pages -Publisher
MDPI
DOI: 10.3390/ijms21155368
Keywords
Niemann-Pick disease; type C1; NPC1; single cell RNA sequencing; transcriptome; cerebellum; cerebellar ataxia
Funding
- intramural research programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [ZIA HD000139]
- National Human Genome Research Institute
- National Institute of Arthritis and Musculoskeletal and Skin Disease
- Ara Parseghian Medical Research Foundation
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Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease characterized by endolysosomal storage of unesterified cholesterol and decreased cellular cholesterol bioavailability. A cardinal symptom of NPC1 is cerebellar ataxia due to Purkinje neuron loss. To gain an understanding of the cerebellar neuropathology we obtained single cell transcriptome data from control (Npc1(+/+)) and both three-week-old presymptomatic and seven-week-old symptomatic mutant (Npc1(-/-)) mice. In seven-week-oldNpc1(-/-)mice, differential expression data was obtained for neuronal, glial, vascular, and myeloid cells. As anticipated, we observed microglial activation and increased expression of innate immunity genes. We also observed increased expression of innate immunity genes by other cerebellar cell types, including Purkinje neurons. Whereas neuroinflammation mediated by microglia may have both neuroprotective and neurotoxic components, the contribution of increased expression of these genes by non-immune cells to NPC1 pathology is not known. It is possible that dysregulated expression of innate immunity genes by non-immune cells is neurotoxic. We did not anticipate a general lack of transcriptomic changes in cells other than microglia from presymptomatic three-week-oldNpc1(-/-)mice. This observation suggests that microglia activation precedes neuronal dysfunction. The data presented in this paper will be useful for generating testable hypotheses related to disease progression and Purkinje neurons loss as well as providing insight into potential novel therapeutic interventions.
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