Neurologic Abnormalities in Mouse Models of the Lysosomal Storage Disorders Mucolipidosis II and Mucolipidosis III c

UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase is an a2b2c2 hexameric enzyme that catalyzes the synthesis of the mannose 6-phosphate targeting signal on lysosomal hydrolases. Mutations in the a/b subunit precursor gene cause the severe lysosomal storage disorder mucolipidosis II (ML II) or the more moderate mucolipidosis III alpha/beta (ML III a/b), while mutations in the c subunit gene cause the mildest disorder, mucolipidosis III gamma (ML III c). Here we report neurologic consequences of mouse models of ML II and ML III c. 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 c 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 c 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. Citation: Idol RA, Wozniak DF, Fujiwara H, Yuede CM, Ory DS, et al. (2014) Neurologic Abnormalities in Mouse Models of the Lysosomal Storage Disorders Mucolipidosis II and Mucolipidosis III c. PLoS ONE 9(10): e109768. doi:10.1371/journal.pone.0109768 Editor: Sheila Fleming, University of Cincinnati, United States of America Received June 25, 2014; Accepted September 12, 2014; Published October 14, 2014 Copyright: 2014 Idol et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information Files. Funding: This work was supported by National Institutes of Health Grant CA08759 to SK, Washington University Intellectual and Developmental Disabilities Research Center P30 HD062171 to DFW, Washington University Metabolomics Facility P30 DK020579 to DSO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: [email protected]