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Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1

  • Original Article
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Journal of Inherited Metabolic Disease

Abstract

Niemann-Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post-mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C-X-C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL-3, IL-10 and IL-13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.

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Acknowledgements

Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. This study was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by the National Institute of Neurological Disorders and Stroke (R01 NS063967 to APL). Support for this work was also provided by Bench-to-Bedside awards from the NIH Clinical Center and Office of Rare Diseases. Research was supported in part by a grant from the National Niemann-Pick Disease Foundation to SMC. NMY was supported by the Ara Parseghian Medical Research Foundation (APMRF). APMRF also supported the collection of control CSF samples which were facilitated by the efforts of Dr. Cyndi Tifft. The authors would also like to acknowledge the contribution of the caretakers, the patients and their families, who participated in this study.

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Authors and Affiliations

  1. Program in Developmental Endocrinology and Genetics, Section on Molecular Dysmorphology, NICHD, NIH, DHHS, Bld. 10, Rm. 9D42, 10 Center Dr, Bethesda, MD, 20892, USA

    Stephanie M. Cologna, Celine V. M. Cluzeau, Nicole M. Yanjanin, Michelle K. Dail, Stephan Siebel, Cynthia L. Toth, Christopher A. Wassif & Forbes D. Porter

  2. Program in Physical Biology, Section on Membrane & Cellular Biophysics, NICHD, NIH, DHHS, Bethesda, MD, 20892, USA

    Paul S. Blank

  3. Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA

    Andrew P. Lieberman

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  1. Stephanie M. Cologna
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  2. Celine V. M. Cluzeau
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  3. Nicole M. Yanjanin
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  4. Paul S. Blank
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  5. Michelle K. Dail
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  6. Stephan Siebel
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  7. Cynthia L. Toth
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  8. Christopher A. Wassif
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  9. Andrew P. Lieberman
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  10. Forbes D. Porter
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Correspondence to Forbes D. Porter.

Additional information

Communicated by: Maurizio Scarpa

Stephanie M. Cologna and Celine V. M. Cluzeau contributed equally to this work.

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Cologna, S.M., Cluzeau, C.V.M., Yanjanin, N.M. et al. Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1. J Inherit Metab Dis 37, 83–92 (2014). https://doi.org/10.1007/s10545-013-9610-6

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