Ultrastructural analysis of neuronal and non-neuronal lysosomal storage in mucolipidosis type II knock-in mice

TY - JOUR

T1 - Ultrastructural analysis of neuronal and non-neuronal lysosomal storage in mucolipidosis type II knock-in mice

AU - Schweizer, Michaela

AU - Markmann, Sandra

AU - Braulke, Thomas

AU - Kollmann, Katrin

PY - 2013/10/1

Y1 - 2013/10/1

N2 - The GlcNAc-1-phosphotransferase catalyzes the first step in the formation of mannose 6-phosphate (M6P) residues on lysosomal acid hydrolases that is essential for the efficient transport of newly synthesized lysosomal enzymes to lysosomes and the maintenance of lysosomal functions. Mutations in the GlcNAc-1-phosphotransferase cause the lysosomal storage disease mucolipidosis type II (MLII), resulting in mistargeting and hypersecretion of multiple lysosomal hydrolases and subsequent lysosomal accumulation of nondegraded material in several tissues. To describe cell-type specificity, compositional differences, and subcellular distribution of the stored material we performed an in-depth ultrastructural analysis of lysosomal storage in brain and retina of MLII knock-in mice using electron microscopy. Massive vacuoles filled with heterogeneous storage material have been found in the soma, swollen axons, and dendrites of Purkinje, and granular cells in 9-month-old MLII mice. In addition, non-neuronal cells, such as microglial, astroglial, and endothelial cells, exhibit storage material. Fucose-specific lectin histochemistry demonstrated the accumulation of fucose-containing oligosaccharides, indicating that targeting of the lysosomal α-fucosidase is strongly impaired in all cerebellar cell types. The data suggest that the accumulation of storage material might affect neuronal function and survival in a direct cell-autonomous manner, as well as indirectly by disturbed metabolic homeostasis between glial and neuronal cells or by cerebrovascular complications.

AB - The GlcNAc-1-phosphotransferase catalyzes the first step in the formation of mannose 6-phosphate (M6P) residues on lysosomal acid hydrolases that is essential for the efficient transport of newly synthesized lysosomal enzymes to lysosomes and the maintenance of lysosomal functions. Mutations in the GlcNAc-1-phosphotransferase cause the lysosomal storage disease mucolipidosis type II (MLII), resulting in mistargeting and hypersecretion of multiple lysosomal hydrolases and subsequent lysosomal accumulation of nondegraded material in several tissues. To describe cell-type specificity, compositional differences, and subcellular distribution of the stored material we performed an in-depth ultrastructural analysis of lysosomal storage in brain and retina of MLII knock-in mice using electron microscopy. Massive vacuoles filled with heterogeneous storage material have been found in the soma, swollen axons, and dendrites of Purkinje, and granular cells in 9-month-old MLII mice. In addition, non-neuronal cells, such as microglial, astroglial, and endothelial cells, exhibit storage material. Fucose-specific lectin histochemistry demonstrated the accumulation of fucose-containing oligosaccharides, indicating that targeting of the lysosomal α-fucosidase is strongly impaired in all cerebellar cell types. The data suggest that the accumulation of storage material might affect neuronal function and survival in a direct cell-autonomous manner, as well as indirectly by disturbed metabolic homeostasis between glial and neuronal cells or by cerebrovascular complications.

KW - Animals

KW - Biological Markers

KW - Cell Survival

KW - Cerebellum

KW - Disease Models, Animal

KW - Gene Knock-In Techniques

KW - Genetic Predisposition to Disease

KW - Lectins

KW - Lysosomes

KW - Mice

KW - Mice, 129 Strain

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Mucolipidoses

KW - Mutation

KW - Neurons

KW - Phenotype

KW - Retina

KW - Transferases (Other Substituted Phosphate Groups)

U2 - 10.3109/01913123.2013.810687

DO - 10.3109/01913123.2013.810687

M3 - SCORING: Journal article

C2 - 24047352

VL - 37

SP - 366

EP - 372

JO - ULTRASTRUCT PATHOL

JF - ULTRASTRUCT PATHOL

SN - 0191-3123

IS - 5

ER -