Peroxisomal multifunctional protein-2 deficiency causes motor deficits and glial lesions in the adult central nervous system.
In humans, mutations inactivating multifunctional protein-2 (MFP-2), and thus peroxisomal beta-oxidation, cause neuronal heterotopia and demyelination, which is clinically reflected by hypotonia, seizures, and death within the first year of life. In contrast, our recently generated MFP-2-deficient mice did not show neurodevelopmental abnormalities but exhibited aberrations in bile acid metabolism and one of three of them died early postnatally. In the postweaning period, all survivors developed progressive motor deficits, including abnormal cramping reflexes of the limbs and loss of mobility, with death at 6 months. Motor impairment was not accompanied by lesions of peripheral nerves or muscles. However, in the central nervous system MFP-2-deficient mice overexpressed catalase in glial cells, accumulated lipids in ependymal cells and in the molecular layer of the cerebellum, exhibited severe astrogliosis and reactive microglia predominantly within the gray matter of the brain and the spinal cord, whereas synaptic and myelin markers were not affected. This culminated in degenerative changes of astroglia cells but not in overt neuronal lesions. Neither the motor deficits nor the brain lesions were aggravated by increasing the branched-chain fatty acid concentration through dietary supplementation. These data indicate that MFP-2 deficiency in mice causes a neurological phenotype in adulthood that is manifested primarily by astroglial damage.
Huyghe
Steven
S
Laboratory of Clinical Chemistry, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Schmalbruch
Henning
H
Hulshagen
Leen
L
Veldhoven
Paul Van
PV
Baes
Myriam
M
Hartmann
Dieter
D
D015067:17-Hydroxysteroid Dehydrogenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology*; D004746:Enoyl-CoA Hydratase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004805:Ependyma / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D018901:Peroxisomal Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064029:Peroxisomal Multifunctional Protein-2; D020675:Peroxisomes / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
D008055:Lipids; D009097:Multienzyme Complexes; D015067:17-Hydroxysteroid Dehydrogenases; C491288:Hsd17b4 protein, mouse; D002374:Catalase; D064029:Peroxisomal Multifunctional Protein-2; D004746:Enoyl-CoA Hydratase