Genomic Expression Analyses Reveal Lysosomal, Innate Immunity Proteins, as Disease Correlates in Murine Models of a Lysosomal Storage Disorder

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.

Ribosome profiling of selenoproteins in vivo reveals consequences of pathogenic Secisbp2 missense mutations

“…express a large number of selenoproteins and thus are ideally suited to address this question (36). The Secisbp2 R543Q protein retains sufficient function to avoid an acute neurodegeneration.…”

Identification of Novel Pathways Associated with Patterned Cerebellar Purkinje Neuron Degeneration in Niemann-Pick Disease, Type C1

“…Sixty-six genes were commonly up/downregulated between lobules III, VI, and X of Npc1 +/+ and Npc1 −/− mice, with six genes being downregulated and 60 genes being upregulated in all Npc1 −/− lobules (Supplementary Materials Figure S2B and Table S1). Of the 60 genes that were significantly upregulated, multiple genes have been previously described as upregulated in the whole cerebellum of Npc1 −/− mice (Ctss, Cybb, Itgax, Itgb2, Gpnmb, Lyz2, Stab1, Icam1, C1qa, C1qb) [35,36], the whole brain of Npc1 −/− mice (Clec7a, Mpeg1, Cd84, C4b, C3ar1, Trem2) [37], used for biomarkers of NPC1 (Lgals3 and Ctsd) [35], or as a marker for dysregulated microglia in Npc1 −/− mice (Cd22) [38]. In almost all instances, the genes with upregulated expression in all lobules have been described as having a direct or indirect function related to the immune response.…”

Lipidomic Analysis Reveals Altered Fatty Acid Metabolism in the Liver of the Symptomatic Niemann–Pick, Type C1 Mouse Model

“…Another microarray study by Alam et al. in multiple tissue types reported alterations in lysosomal and innate immunity proteins . Further, enzymes associated with drug metabolism and related toxicity have also been reported as altered .…”