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 (Npc1+/+) and both three-week-old presymptomatic and seven-week-old symptomatic mutant (Npc1−/−) mice. In seven-week-old Npc1−/− 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 Npc1−/− 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.
Highlights
Niemann–Pick disease, type C1 (NPC1, MIM #257220) is a rare neurodegenerative disease caused by reduced function of NPC1 [1]
To gain insight into pathological processes occurring in individual cerebellar cell types we performed single cell RNA sequencing on cerebellar tissue collected from asymptomatic three-week-old and symptomatic seven-week-old male Npc1−/− (BALB/Npc1m1N) and corresponding control Npc1+/+ littermates
Based on expression of signature transcripts, we identified transcriptomes corresponding to myeloid cells, vascular cells, glial cells and neurons
Summary
Niemann–Pick disease, type C1 (NPC1, MIM #257220) is a rare neurodegenerative disease caused by reduced function of NPC1 [1]. Purkinje neurons are large inhibitory GABAergic neurons that function to integrate cerebellar neuronal input and provide the sole output of the cerebellum via axons that project to the deep cerebellar nuclei. Found in the molecular layer, synapse on the Purkinje neuron cell and provide inhibitory input. Cerebellar ataxia in NPC1 results from the progressive loss of cerebellar Purkinje neurons. Npc expression in astrocytes significantly increases survival for Npc1−/− mice, suggesting glial cells dysfunction is involved in disease progression [17]. To gain insight into pathological processes occurring in individual cerebellar cell types we performed single cell RNA sequencing (scRNAseq) on cerebellar tissue collected from asymptomatic three-week-old and symptomatic seven-week-old male Npc1−/− (BALB/Npc1m1N) and corresponding control Npc1+/+ littermates. Understanding the individual cellular contributions to NPC1 pathology may lead to therapeutic approaches targeting various aspects of the pathological cascade
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