Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities

Jakub Sikora, Shaalee Dworski, E. Ellen Jones, Mustafa A. Kamani, Matthew C. Micsenyi, Tomo Sawada, Pauline Le Faouder, Justine Bertrand-Michel, Aude Dupuy, Christopher K. Dunn, Ingrid Cong Yang Xuan, Josefina Casas, Gemma Fabrias, David R. Hampson, Thierry Levade, Richard R. Drake, Jeffrey A. Medin, Steven U. Walkley

Research output: Contribution to journalArticle

Abstract

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 Asah1P361R/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 Asah1P361R/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.

Original languageEnglish (US)
Pages (from-to)864-883
Number of pages20
JournalAmerican Journal of Pathology
Volume187
Issue number4
DOIs
StatePublished - Apr 1 2017

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Farber Lipogranulomatosis
Nervous System Malformations
Central Nervous System
Ceramides
Microglia
Mass Spectrometry
Macrophages
Meninges
Sphingosine
Choroid Plexus
Autonomic Nervous System
Muscle Strength
Hand Strength
Locomotion
Hydrocephalus
Granuloma
Nervous System Diseases
Endothelial Cells
Neurons
Brain

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities. / Sikora, Jakub; Dworski, Shaalee; Jones, E. Ellen; Kamani, Mustafa A.; Micsenyi, Matthew C.; Sawada, Tomo; Le Faouder, Pauline; Bertrand-Michel, Justine; Dupuy, Aude; Dunn, Christopher K.; Xuan, Ingrid Cong Yang; Casas, Josefina; Fabrias, Gemma; Hampson, David R.; Levade, Thierry; Drake, Richard R.; Medin, Jeffrey A.; Walkley, Steven U.

In: American Journal of Pathology, Vol. 187, No. 4, 01.04.2017, p. 864-883.

Research output: Contribution to journalArticle

Sikora, J, Dworski, S, Jones, EE, Kamani, MA, Micsenyi, MC, Sawada, T, Le Faouder, P, Bertrand-Michel, J, Dupuy, A, Dunn, CK, Xuan, ICY, Casas, J, Fabrias, G, Hampson, DR, Levade, T, Drake, RR, Medin, JA & Walkley, SU 2017, 'Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities' American Journal of Pathology, vol 187, no. 4, pp. 864-883. DOI: 10.1016/j.ajpath.2016.12.005
Sikora J, Dworski S, Jones EE, Kamani MA, Micsenyi MC, Sawada T et al. Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities. American Journal of Pathology. 2017 Apr 1;187(4):864-883. Available from, DOI: 10.1016/j.ajpath.2016.12.005

Sikora, Jakub; Dworski, Shaalee; Jones, E. Ellen; Kamani, Mustafa A.; Micsenyi, Matthew C.; Sawada, Tomo; Le Faouder, Pauline; Bertrand-Michel, Justine; Dupuy, Aude; Dunn, Christopher K.; Xuan, Ingrid Cong Yang; Casas, Josefina; Fabrias, Gemma; Hampson, David R.; Levade, Thierry; Drake, Richard R.; Medin, Jeffrey A.; Walkley, Steven U. / Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities.

In: American Journal of Pathology, Vol. 187, No. 4, 01.04.2017, p. 864-883.

Research output: Contribution to journalArticle

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