Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B.
The neurodegenerative disease MPS III B (Sanfilippo syndrome type B) is caused by mutations in the gene encoding the lysosomal enzyme alpha-N-acetylglucosaminidase, with a resulting block in heparan sulfate degradation. A mouse model with disruption of the Naglu gene allows detailed study of brain pathology. In contrast to somatic cells, which accumulate primarily heparan sulfate, neurons accumulate a number of apparently unrelated metabolites, including subunit c of mitochondrial ATP synthase (SCMAS). SCMAS accumulated from 1 month of age, primarily in the medial entorhinal cortex and layer V of the somatosensory cortex. Its accumulation was not due to the absence of specific proteases. Light microscopy of brain sections of 6-months-old mice showed SCMAS to accumulate in the same areas as glycosaminoglycan and unesterified cholesterol, in the same cells as ubiquitin and GM3 ganglioside, and in the same organelles as Lamp 1 and Lamp 2. Cryo-immuno electron microscopy showed SCMAS to be present in Lamp positive vesicles bounded by a single membrane (lysosomes), in fingerprint-like layered arrays. GM3 ganglioside was found in the same lysosomes, but was not associated with the SCMAS arrays. GM3 ganglioside was also seen in lysosomes of microglia, suggesting phagocytosis of neuronal membranes. Samples used for cryo-EM and further processed by standard EM procedures (osmium tetroxide fixation and plastic embedding) showed the disappearance of the SCMAS fingerprint arrays and appearance in the same location of "zebra bodies", well known but little understood inclusions in the brain of patients with mucopolysaccharidoses.
Ryazantsev
Sergey
S
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1737, USA.
Yu
Wei-Hong
WH
Zhao
Hui-Zhi
HZ
Neufeld
Elizabeth F
EF
Ohmi
Kazuhiro
K
D000375:Aging; D000818:Animals; D020285:Cryoelectron Microscopy; D004195:Disease Models, Animal; D005679:G(M3) Ganglioside / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D009084:Mucopolysaccharidosis III / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism* / Q000648:ultrastructure; D013003:Somatosensory Cortex / Q000378:metabolism* / Q000648:ultrastructure; D052118:Lysosomal-Associated Membrane Protein 1
D005679:G(M3) Ganglioside; D006025:Glycosaminoglycans; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D025261:Mitochondrial Proton-Translocating ATPases; D021122:Protein Subunits; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1