Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities.
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/P361Rmice, 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/P361Rmice 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.
Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York; Institute of Inherited Metabolic Disorders, Charles University, 1st Faculty of Medicine, Prague, Czech Republic; Institute of Pathology, Charles University, 1st Faculty of Medicine, Prague, Czech Republic.
Jakub
J
Sikora
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Shaalee
S
Dworski
Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina.
E Ellen
EE
Jones
University Health Network, Toronto, Ontario, Canada.
Mustafa A
MA
Kamani
Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York.
Matthew C
MC
Micsenyi
Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York.
Tomo
T
Sawada
MetaToul-Lipidomic Facility-MetaboHUB, INSERM UMR1048, Institute of Cardiovascular and Metabolic Diseases, Université Paul Sabatier-Toulouse III, Toulouse, France.
Pauline
P
Le Faouder
MetaToul-Lipidomic Facility-MetaboHUB, INSERM UMR1048, Institute of Cardiovascular and Metabolic Diseases, Université Paul Sabatier-Toulouse III, Toulouse, France.
Justine
J
Bertrand-Michel
MetaToul-Lipidomic Facility-MetaboHUB, INSERM UMR1048, Institute of Cardiovascular and Metabolic Diseases, Université Paul Sabatier-Toulouse III, Toulouse, France.
Aude
A
Dupuy
University Health Network, Toronto, Ontario, Canada.
Christopher K
CK
Dunn
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
Ingrid Cong Yang
ICY
Xuan
Research Unit on Bioactive Molecules, Department of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia, Spanish National Research Council, Barcelona, Spain.
Josefina
J
Casas
Research Unit on Bioactive Molecules, Department of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia, Spanish National Research Council, Barcelona, Spain.
Gemma
G
Fabrias
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
David R
DR
Hampson
INSERM UMR1037, Cancer Research Center of Toulouse, Universite Toulouse III Paul-Sabatier, Toulouse, France; Metabolic Biochemistry Laboratory, Federative Institute of Biology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
Thierry
T
Levade
Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina.
Richard R
RR
Drake
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address: jmedin@mcw.edu.
Jeffrey A
JA
Medin
Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, New York. Electronic address: steve.walkley@einstein.yu.edu.
Steven U
SU
Walkley
D055573:Acid Ceramidase / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D002490:Central Nervous System / Q000002:abnormalities* / Q000473:pathology; D002531:Cerebellum / Q000473:pathology / Q000648:ultrastructure; D054022:Cerebrum / Q000473:pathology / Q000648:ultrastructure; D055577:Farber Lipogranulomatosis / Q000150:complications* / Q000473:pathology*; D006720:Homozygote; D006849:Hydrocephalus / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009421:Nervous System Malformations / Q000209:etiology* / Q000473:pathology*; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013107:Sphingolipids / Q000378:metabolism; D013997:Time Factors
D013107:Sphingolipids; D055573:Acid Ceramidase; C526734:Asah1 protein, mouse