Plasma signature of neurological disease in the monogenetic disorder Niemann-Pick Type C.
Early diagnosis of neurological disorders would greatly improve their management and treatment. A major hurdle is that inflammatory products of cerebral disease are not easily detected in blood. Inflammation in multiple organs and heterogeneity in disease present additional challenges in distinguishing the extent to which a blood-based marker reflects disease in brain or other afflicted organs. Murine models of the monogenetic disorder Niemann-Pick Type C present aggressive forms of cerebral and liver inflammatory disease. Microarray analyses previously revealed age-dependent changes in innate immunity transcripts in the mouse brain. We have now validated four putative secretory inflammatory markers that are also elevated in mouse liver. We include limited, first time analysis of human Niemann-Pick Type C liver and cerebellum. Furthermore, we utilized 2-hydroxypropyl-β-cyclodextrin (HPβCD, an emerging therapeutic) administered intraperitoneally in mice, which abrogates inflammatory pathology in the liver but has limited effect on the brain. By analyzing the corresponding effects on inflammatory plasma proteins, we identified cathepsin S as a lead indicator of liver disease. In contrast, lysozyme was a marker of both brain and liver disease. 2-Hydroxypropyl-β-cyclodextrin had no effect on transcripts of neuron-specific 24-hydroxylase, and its product 24(S)-hydroxycholesterol was not a useful indicator in mouse plasma. Our data suggest that dual analysis of levels of the inflammatory markers lysozyme and cathepsin S may enable detection of multiple distinct states of neurodegeneration in plasma.
From the Center for Rare and Neglected Diseases and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556.
Md Suhail
MS
Alam
Michelle
M
Getz
Sue
S
Yi
Jeffrey
J
Kurkewich
Innocent
I
Safeukui
Kasturi
K
Haldar
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002403:Cathepsins / Q000032:analysis* / Q000097:blood* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009113:Muramidase / Q000097:blood* / Q000276:immunology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000097:blood* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D011506:Proteins / Q000235:genetics; D047392:beta-Cyclodextrins / Q000627:therapeutic use
D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D009113:Muramidase; D002403:Cathepsins; C028217:cathepsin S
Biomarkers; Cathepsin S; Genetic Diseases; Inflammation; Lysozyme; Neurodegeneration; Neuroinflammation