Single Cell Transcriptome Analysis of Niemann-Pick Disease, Type C1 Cerebella.

Int J Mol Sci

Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Published: July 2020

AI Article Synopsis

  • * Researchers analyzed single-cell transcriptome data from mutant mice at different ages to understand cerebellar neuropathology, finding increased activation of microglia and expression of innate immunity-related genes in symptomatic mice.
  • * The study suggests that microglial activation occurs before observable neuronal dysfunction, raising questions about the potential neurotoxic effects of immune response genes in non-immune cells and offering avenues for future therapeutic research.

Article Abstract

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 () and both three-week-old presymptomatic and seven-week-old symptomatic mutant () mice. In seven-week-old 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-old 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432835PMC
http://dx.doi.org/10.3390/ijms21155368DOI Listing

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