Marjorie C. Gondré-Lewis, Robert McGlynn, Steven U. Walkley

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Cholesterol Accumulation in NPC1-Deficient Neurons Is Ganglioside Dependent Marjorie C. Gondré-Lewis, Robert McGlynn, Steven U. Walkley Current Biology Volume 13, Issue 15, Pages 1324-1329 (August 2003) DOI: 10.1016/S0960-9822(03)00531-1

Figure 1 Cholesterol Expression Was Analyzed in the Cerebrum and Cerebellum of NPC1−/− Mice Lacking Complex Gangliosides Mice heterozygous for the NPC1 mutation and the GalNAcT deletion were crossed to generate double mutant NPC1−/− mice unable to synthesize higher order gangliosides. (A) Filipin was used to stain for unesterified cholesterol (white) in cerebral cortex (top panel) and hippocampus (bottom panel). Cholesterol was not accumulated in normal wild-type (WT) brains (left panel), but was stored throughout neurons of NPC-affected brains (middle) and to a considerably lesser extent in double-deficient mouse brains (right panel). (B) Analysis of unesterified cholesterol in cerebella of NPC1−/− (middle panel) and double-deficient animals (bottom panel) showed no difference in distribution as both exhibited numerous filipin-positive profiles throughout the cerebellar cortex, and particularly in the molecular layer. Arrows illustrate Purkinje neurons that are still present and laden with unesterified cholesterol. As expected, WT mice (top panel) do not abnormally sequester unesterified cholesterol within cell bodies. Bar = 120 μm for upper panels of (A) and 80 μm for lower panels of (A); Bar in (B) = 200 μm. Current Biology 2003 13, 1324-1329DOI: (10.1016/S0960-9822(03)00531-1)

Figure 2 Regional Expression of GM3 Ganglioside and Unesterified Cholesterol Were Compared in Cerebral Cortex and Hippocampus Analysis of the expression of the simple ganglioside, GM3, in NPC−/− (A, left) and double-deficient mouse cerebral cortex (A, right) showed no obvious compensatory increase in GM3 expression when GalNAcT was absent. The expression of GM3 ganglioside (brown) was assessed in situ by immunocytochemistry and compared to unesterified cholesterol (white) determined by filipin staining in different brain regions. In cortex (B) as well as in the CA1 (C) and CA3 (D) regions of the hippocampus, unesterified cholesterol expression (right panels) was proportional to ganglioside expression (left panels). Notably, in CA1 neurons where little to no GM3 accumulation was found, cholesterol was also absent; in CA3 neurons where GM3 was abundant, cholesterol accumulation was conspicuous. Bar = 70 μm for (A); 63 μm for (B), (C), and (D). Current Biology 2003 13, 1324-1329DOI: (10.1016/S0960-9822(03)00531-1)

Figure 3 Coexpression of Cholesterol and GM3 Ganglioside in Layer V Pyramidal Neurons of Double-Deficient Mouse Cerebral Cortex Double labeling with an antibody to GM3 (red) and filipin histochemistry (blue) was performed on 15 μm sections of double-deficient mouse cerebral cortex and analyzed by fluorescence microscopy. Examples of neuronal nuclei are demarcated with an asterisk (*). Some neurons exhibiting GM3 storage did not demonstrate cholesterol storage in the same plane (inset A, arrowheads), but cell profiles positive for filipin and lacking GM3 were not observed. Cholesterol storage was localized to the same neurons as GM3 in meganeurites (arrows) and in associated cell bodies of layer V pyramidal neurons (inset B). Bar = 60 μm for left panel; 20 μm for insets A and B. Current Biology 2003 13, 1324-1329DOI: (10.1016/S0960-9822(03)00531-1)

Figure 4 Cholesterol and GM3 Ganglioside Coexpression Was Analyzed in Purkinje Neurons of Double-Deficient Mice versus NPC1−/− Mice Double labeling with antibody to GM3 (red) and filipin (blue) was performed on 15 μm sections of cerebellum and analyzed by fluorescence microscopy. Cholesterol storage was abundant in Purkinje cells of 5-week-old double-deficient (A, B inset) and in NPC1−/− mice (C). Purkinje cells in double-deficient animals also exhibited GM3 accumulation in association with filipin-reactive regions of the perikarya (B, arrows) whereas age-matched NPC1−/− Purkinje cells exhibited no GM3 immunoreactivity in conjunction with cholesterol storage (C). Bar = 13 μm and applies to (A). Current Biology 2003 13, 1324-1329DOI: (10.1016/S0960-9822(03)00531-1)