Ultrastructural analysis of neuronal and non-neuronal lysosomal storage in mucolipidosis type II knock-in mice
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Ultrastructural analysis of neuronal and non-neuronal lysosomal storage in mucolipidosis type II knock-in mice. / Schweizer, Michaela; Markmann, Sandra; Braulke, Thomas; Kollmann, Katrin.
in: ULTRASTRUCT PATHOL, Jahrgang 37, Nr. 5, 01.10.2013, S. 366-72.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -