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.

Hard X‐Ray Nanoholotomography: Large‐Scale, Label‐Free, 3D Neuroimaging beyond Optical Limit

“…For example, many pathological brain conditions are associated with cell loss,26 abnormal cellular, or dendritic morphology 27. Similarly, changes at the subcellular level have been reported for neurodegenerative disorders, for example, membrane damage inducing curvature adaptation,28 axon demyelination, and abnormal morphology of microglia in Alzheimer's disease.…”

Enzyme-specific differences in mannose phosphorylation between GlcNAc-1-phosphotransferase αβ and γ subunit deficient zebrafish support cathepsin proteases as early mediators of mucolipidosis pathology

“…Analyses of Gnptab and Gnptg null mice have demonstrated differences in the phenotypic consequences associated with loss of the two genes (19,20). In particular, cellular lesions were not only less severe but also more restricted in Gnptg −/− mice.…”

Knockout of Lysosomal Enzyme-Targeting Gene Causes Abnormalities in Mouse Pup Isolation Calls

“…A mouse model of Mucolipidosis with a knockout of GNPTAB has been identified and studied (Gelfman et al, 2007; Idol et al, 2014; Paton et al, 2014). Gnptab −/− mice have been found to have progressive neurodegeneration including neuronal loss, astrocytosis, microgliosis and Purkinje cell depletion that was evident as early as 4 months (Idol et al, 2014).…”

“…Gnptab −/− mice have been found to have progressive neurodegeneration including neuronal loss, astrocytosis, microgliosis and Purkinje cell depletion that was evident as early as 4 months (Idol et al, 2014). Gnptab −/− mice were found to have a total loss of acid hydrolase phosphorylation, which results in depletion of acid hydrolases in mesenchymal-derived cells (Gelfman et al, 2007; Idol et al, 2014; Paton et al, 2014).…”

“…Gnptab −/− mice have been found to have progressive neurodegeneration including neuronal loss, astrocytosis, microgliosis and Purkinje cell depletion that was evident as early as 4 months (Idol et al, 2014). Gnptab −/− mice were found to have a total loss of acid hydrolase phosphorylation, which results in depletion of acid hydrolases in mesenchymal-derived cells (Gelfman et al, 2007; Idol et al, 2014; Paton et al, 2014). Behaviorally, Gnptab −/− mice, at 1 month of age, were found to perform normally on a 1 h locomotor activity test, but were found to be behaviorally impaired on tests such as how long mice remained on an elevated platform or accelerating rotorod, how long mice took to climb down a pole, and other sensory motor tests (Idol et al, 2014; Paton et al, 2014).…”