Abstract
Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1−/− mice relative to Npc1+/− at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher’s disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1−/− as well as Balb/c Npc1nmf164 mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1−/− mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1 −/− spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation.
Highlights
Niemann-Pick Type C (NPC) is a neurodegenerative, lysosomal disorder caused by defects in function of either genes Npc1 or Npc2, in 95% of patients disease is caused by defect in Npc1 [1]
We report for the first time, neutrophil elevation in liver and spleen of Npc12/2 mice that may play a role in NPC pathophysiology and disease exacerbation
Advanced Neurodegeneration Progressive neurological dysfunction is a prominent feature of NPC disease, and understanding correlates in the brain is of critical importance to understanding disease progression
Summary
Niemann-Pick Type C (NPC) is a neurodegenerative, lysosomal disorder caused by defects in function of either genes Npc or Npc, in 95% of patients disease is caused by defect in Npc1 [1]. Inflammatory changes have been reported in the liver, spleen and brain of NPC animals [2,3,4,5] and anti-inflammatory treatments have been shown to reduce disease burden in mice [4,6]. Comprehensive, unbiased, genome wide analyses of changes in gene expression in a leading organ of interest, the brain, across the life span, especially as animals transition from a phenotypically asymptomatic state to manifesting major disease symptoms, is not yet available. Further whether age-dependent gene expression in the brain is linked if at all, to that in the liver and/or spleen two organs that manifest early disease symptoms, is not known. Genes expressed in an age-dependent manner in both brain and liver (the source of plasma proteins) would facilitate identification of blood-based biomarkers that reflect cerebral disease
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