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Characterization of the visceral and neuronal phenotype of 4L/PS-NA mice modeling Gaucher disease

Schiffer, Victoria, Santiago-Mujika, Estibaliz, Flunkert, Stefanie, Schmidt, Staffan, Farcher, Martina, Loeffler, Tina, Schilcher, Irene, Posch, Maria, Neddens, Joerg, Sun, Ying, Kehr, Jan, Hutter-Paier, Birgit·2020·PLOS ONE
DOI 10.1371/journal.pone.0227077PMC PMC6957154
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Fig 1 General health and motor deficits of 4L/PS-NA mice over age. Eight, 12 and 18 week old 4L/PS-NA mice and control littermates were analyzed for body weight (A), the hanging time in seconds in the wire suspension test (B), the total number of slips (C) and the active time in the beam walk test (D), the latency to fall off the rotating rod of the Rota Rod test (E) and the number of bites per episode in the pasta gnawing test (F). Two-way ANOVA followed by Bonferroni’s post hoc test. n = 7 per group. Mean ± SEM. *differences between genotypes; #differences between age groups; *p<0.05; **p<0.01; ***p<0.001.
Fig 1 General health and motor deficits of 4L/PS-NA mice over age. Eight, 12 and 18 week old 4L/PS-NA mice and control littermates were analyzed for body weight (A), the hanging time in seconds in the wire suspension test (B), the total number of slips (C) and the active time in the beam walk test (D), the latency to fall off the rotating rod of the Rota Rod test (E) and the number of bites per episode in the pasta gnawing test (F). Two-way ANOVA followed by Bonferroni’s post hoc test. n = 7 per group. Mean ± SEM. *differences between genotypes; #differences between age groups; *p<0.05; **p<0.01; ***p<0.001.CC BY · PubMed Central
Fig 2 Tissue weight of 4L/PS-NA mice over age. Tissue weight of liver (A), lung (B), spleen (C), thymus (D), cerebellum (left hemisphere, E) and left brain hemisphere without cerebellum (F) were measured at 5, 12, or 18 week of age. Two-way ANOVA followed by Bonferroni’s post hoc test. 4L/PS-NA: 5 weeks: n = 6; 12 weeks: n = 7; 18 weeks: n = 15; Control: 5 weeks: n = 5; 12 weeks: n = 7; 18 weeks: n = 16; Mean + SEM. *differences between genotypes; #differences between age groups; *p<0.05; **p<0.01; ***p<0.001.
Fig 2 Tissue weight of 4L/PS-NA mice over age. Tissue weight of liver (A), lung (B), spleen (C), thymus (D), cerebellum (left hemisphere, E) and left brain hemisphere without cerebellum (F) were measured at 5, 12, or 18 week of age. Two-way ANOVA followed by Bonferroni’s post hoc test. 4L/PS-NA: 5 weeks: n = 6; 12 weeks: n = 7; 18 weeks: n = 15; Control: 5 weeks: n = 5; 12 weeks: n = 7; 18 weeks: n = 16; Mean + SEM. *differences between genotypes; #differences between age groups; *p<0.05; **p<0.01; ***p<0.001.CC BY · PubMed Central
Fig 3 Enlarged leukocytes in visceral organs of 4L/PS-NA mice. The liver (A), lung (B), spleen (C) and thymus (D) of 4L/PS-NA mice and control littermates were labeled with CD45 antibody at the age of 5, 12 and 18 weeks; green: CD45; blue: DAPI. Scale bars: Overview: 100 μm, inserts: 10 μm.
Fig 3 Enlarged leukocytes in visceral organs of 4L/PS-NA mice. The liver (A), lung (B), spleen (C) and thymus (D) of 4L/PS-NA mice and control littermates were labeled with CD45 antibody at the age of 5, 12 and 18 weeks; green: CD45; blue: DAPI. Scale bars: Overview: 100 μm, inserts: 10 μm.CC BY · PubMed Central
Fig 4 Enlarged macrophages in visceral organs of 4L/PS-NA mice. The liver (A), lung (B), spleen (C) and thymus (D) of 4L/PS-NA mice and control littermates were labeled with F4/80 antibody at the age of 5, 12 and 18 weeks; green: F4/80; blue: DAPI. Scale bars: Overview: 100 μm, inserts: 10 μm. Arrows indicate enlarged macrophages surrounding alveoles.
Fig 4 Enlarged macrophages in visceral organs of 4L/PS-NA mice. The liver (A), lung (B), spleen (C) and thymus (D) of 4L/PS-NA mice and control littermates were labeled with F4/80 antibody at the age of 5, 12 and 18 weeks; green: F4/80; blue: DAPI. Scale bars: Overview: 100 μm, inserts: 10 μm. Arrows indicate enlarged macrophages surrounding alveoles.CC BY · PubMed Central
Fig 5 Quantification of glucocerebrosidase, glucosylceramide and glucosylsphingosine in 4L/PS-NA mice over age. The cortex of 5, 12 and 18 week old 4L/PS-NA mice, control animals as well as C57Bl/6 mice was analyzed for glucocerebrosidase activity by 4-MUG assay (A). Whole brain homogenates of 5, 12 and 18 week old 4L/PS-NA mice, control animals as well as C57Bl/6 mice were analyzed for glucosylceramide (B) and glucosylsphingosine (C) levels in μg/g wet weight (B) or ng/g wet weight (C). Two-way ANOVA followed by Bonferroni’s post hoc test. Values of C57Bl/6 mice (triangles in B and C) were excluded from all statistical analyses; n = 5 for 4L/PS-NA and control animals; n = 3 for C57Bl/6 mice. Mean + SEM. *differences between genotypes; #differences between age groups; *p<0.05; **p<0.01; ***p<0.001.
Fig 5 Quantification of glucocerebrosidase, glucosylceramide and glucosylsphingosine in 4L/PS-NA mice over age. The cortex of 5, 12 and 18 week old 4L/PS-NA mice, control animals as well as C57Bl/6 mice was analyzed for glucocerebrosidase activity by 4-MUG assay (A). Whole brain homogenates of 5, 12 and 18 week old 4L/PS-NA mice, control animals as well as C57Bl/6 mice were analyzed for glucosylceramide (B) and glucosylsphingosine (C) levels in μg/g wet weight (B) or ng/g wet weight (C). Two-way ANOVA followed by Bonferroni’s post hoc test. Values of C57Bl/6 mice (triangles in B and C) were excluded from all statistical analyses; n = 5 for 4L/PS-NA and control animals; n = 3 for C57Bl/6 mice. Mean + SEM. *differences between genotypes; #differences between age groups; *p<0.05; **p<0.01; ***p<0.001.CC BY · PubMed Central
Fig 6 Quantification of astrocytosis and activated microglia in 4L/PS-NA mice over age. The cortex (A,C) and hippocampus (B,D) of 4L/PS-NA mice was analyzed for GFAP (A,B) and IBA1 (C,D) immunoreactive area (IR) in percent at the age of 5, 12 and 18 weeks compared to control littermates. Two-way ANOVA followed by Bonferroni’s post hoc test. n = 5 per group. Mean + SEM. *differences between genotypes; #differences between age groups; **p<0.01; ***p<0.001. E: Representative images of GFAP, IBA1 and DAPI labeling of the hippocampal CA1 region in 18 week old 4L/PS-NA and control mice. Scale bar: 50 μm.
Fig 6 Quantification of astrocytosis and activated microglia in 4L/PS-NA mice over age. The cortex (A,C) and hippocampus (B,D) of 4L/PS-NA mice was analyzed for GFAP (A,B) and IBA1 (C,D) immunoreactive area (IR) in percent at the age of 5, 12 and 18 weeks compared to control littermates. Two-way ANOVA followed by Bonferroni’s post hoc test. n = 5 per group. Mean + SEM. *differences between genotypes; #differences between age groups; **p<0.01; ***p<0.001. E: Representative images of GFAP, IBA1 and DAPI labeling of the hippocampal CA1 region in 18 week old 4L/PS-NA and control mice. Scale bar: 50 μm.CC BY · PubMed Central
Fig 7 Quantification of α-synuclein and calbindin in 4L/PS-NA mice over age. The cerebellum (A,C) and hippocampus (B,D) of 4L/PS-NA mice was analyzed for pan α-synuclein (A,B) and calbindin (C,D) immunoreactive area (IR) in percent at the age of 5, 12 and 18 weeks compared to control littermates. Two-way ANOVA followed by Bonferroni’s post hoc test. n = 5 per group. Mean + SEM. *differences between genotypes; #differences between age groups; *p<0.05; **p<0.01; ***p<0.001. E: Representative images of pan α-synuclein, calbindin and DAPI labeling of the hippocampal CA1 region in 5 week old 4L/PS-NA and control mice. Scale bar: 50 μm.
Fig 7 Quantification of α-synuclein and calbindin in 4L/PS-NA mice over age. The cerebellum (A,C) and hippocampus (B,D) of 4L/PS-NA mice was analyzed for pan α-synuclein (A,B) and calbindin (C,D) immunoreactive area (IR) in percent at the age of 5, 12 and 18 weeks compared to control littermates. Two-way ANOVA followed by Bonferroni’s post hoc test. n = 5 per group. Mean + SEM. *differences between genotypes; #differences between age groups; *p<0.05; **p<0.01; ***p<0.001. E: Representative images of pan α-synuclein, calbindin and DAPI labeling of the hippocampal CA1 region in 5 week old 4L/PS-NA and control mice. Scale bar: 50 μm.CC BY · PubMed Central
Fig 8 Pathological alterations in the cerebellum of 4L/PS-NA mice. The cerebellum of 18 week old 4L/PS-NA mice (B) and control littermates (A) were labeled with antibodies against α-synuclein (red) and calbindin (green) and nuclei were visualized with DAPI (blue). Scale bar: 1,000 μm. 1, 2, 3 and 4 show magnifications of areas indicated in the overview images. DAPI staining is not shown in higher magnification images. arrow: Purkinje cell axon; ML: molecular layer; PCL: Purkinje cell layer; GCL: granule cell layer; WM: white matter.
Fig 8 Pathological alterations in the cerebellum of 4L/PS-NA mice. The cerebellum of 18 week old 4L/PS-NA mice (B) and control littermates (A) were labeled with antibodies against α-synuclein (red) and calbindin (green) and nuclei were visualized with DAPI (blue). Scale bar: 1,000 μm. 1, 2, 3 and 4 show magnifications of areas indicated in the overview images. DAPI staining is not shown in higher magnification images. arrow: Purkinje cell axon; ML: molecular layer; PCL: Purkinje cell layer; GCL: granule cell layer; WM: white matter.CC BY · PubMed Central

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Cited by

Metadata

Authors
Schiffer, V., Santiago-Mujika, E., Flunkert, S., Schmidt, S., Farcher, M., Loeffler, T., Schilcher, I., Posch, M., Neddens, J., Sun, Y., Kehr, J., & Hutter-Paier, B.
ORCID
Flunkert, Stefanie
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2020-01-13
Volume
15
Issue
1
Pages
e0227077
ISSN
1932-6203
DOI
10.1371/journal.pone.0227077
PMC
PMC6957154
Cited by
11
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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