Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 187, Issue 4, Pages 864-883Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2016.12.005
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Funding
- National Institute of Neurological Diseases and Stroke Award [1F05 NS074790]
- Charles University Research Development Schemes (PRVOUK) grant [P24/LF1/3]
- OPPK grant [CZ.2.16/3.1.00/24509]
- Canadian Institutes of Health Research Biological Therapeutics Traineeship
- NIH [1R21NS078191-01A1, R01 HD045561, P30 HD071593]
- Spanish Ministry of Science and Technology [SAF2011-22444]
- Spanish Ministry of Economy and Competitiveness [CTQ2014-54743-R]
- INSERM
- Vaincre les Maladies Lysosomales
- South Carolina SmartState Endowed Research program
- National Cancer Institute [P30 CA138313]
- South Carolina Clinical and Translational Research Institute [UL1 RR029882, UL1 TR000062]
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Farber disease is a rare autosomal recessive disorder caused by acid ceramidase deficiency that usually presents as early-onset progressive visceral and neurologic disease. To understand the neurologic abnormality, we investigated behavioral, biochemical, and cellular abnormalities in the central nervous system of Asah1(P361R/P361R) mice, which serve as a model of Farber disease. Behaviorally, the mutant mice had reduced voluntary locomotion and exploration, increased thigmotaxis, abnormal spectra of basic behavioral activities, impaired muscle grip strength, and defects in motor coordination. A few mutant mice developed hydrocephalus. Mass spectrometry revealed elevations of ceramides, hydroxy-ceramides, dihydroceramides, sphingosine, dihexosylceramides, and monosialodihexosylganglioside in the brain. The highest accumulation was in hydroxy-ceramides. Storage compound distribution was analyzed by mass spectrometry imaging and morphologic analyses and revealed involvement of a wide range of central nervous system cell types (eg, neurons, endothelial cells, and choroid plexus cells), most notably microglia and/or macrophages. Coalescing and mostly perivascular granuloma-like accumulations of storage-laden CD68(+) microglia and/or macrophages were seen as early as 3 weeks of age and located preferentially in white matter, periventricular zones, and meninges. Neurodegeneration was also evident in specific cerebral areas in late disease. Overall, our central nervous system studies in Asah1(P361R/P361R) mice substantially extend the understanding of human Farber disease and suggest that this model can be used to advance therapeutic approaches for this currently untreatable disorder.
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