title: Neurologic abnormalities in mouse models of the lysosomal storage disorders mucolipidosis II and mucolipidosis III γ.
abstract: UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase is an α2β2γ2 hexameric enzyme that catalyzes the synthesis of the mannose 6-phosphate targeting signal on lysosomal hydrolases. Mutations in the α/β subunit precursor gene cause the severe lysosomal storage disorder mucolipidosis II (ML II) or the more moderate mucolipidosis III alpha/beta (ML III α/β), while mutations in the γ subunit gene cause the mildest disorder, mucolipidosis III gamma (ML III γ). Here we report neurologic consequences of mouse models of ML II and ML III γ. The ML II mice have a total loss of acid hydrolase phosphorylation, which results in depletion of acid hydrolases in mesenchymal-derived cells. The ML III γ mice retain partial phosphorylation. However, in both cases, total brain extracts have normal or near normal activity of many acid hydrolases reflecting mannose 6-phosphate-independent lysosomal targeting pathways. While behavioral deficits occur in both models, the onset of these changes occurs sooner and the severity is greater in the ML II mice. The ML II mice undergo progressive neurodegeneration with neuronal loss, astrocytosis, microgliosis and Purkinje cell depletion which was evident at 4 months whereas ML III γ mice have only mild to moderate astrocytosis and microgliosis at 12 months. Both models accumulate the ganglioside GM2, but only ML II mice accumulate fucosylated glycans. We conclude that in spite of active mannose 6-phosphate-independent targeting pathways in the brain, there are cell types that require at least partial phosphorylation function to avoid lysosomal dysfunction and the associated neurodegeneration and behavioral impairments.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Idol
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: David F
authors.initials: DF
authors.lastname: Wozniak
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Hideji
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Yuede
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Stuart
authors.initials: S
authors.lastname: Kornfeld
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009043:Motor Activity; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009844:Oligosaccharides / Q000378:metabolism; D011596:Psychomotor Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D045442:Rotarod Performance Test; D066191:Sensorimotor Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D005732:Gangliosides; D008840:Microfilament Proteins; D009844:Oligosaccharides; D017855:Transferases (Other Substituted Phosphate Groups); C548056:GNPTAB protein, mouse