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Localization of mutant ubiquitin in the brain of a transgenic mouse line with proteasomal inhibition and its validation at specific sites in Alzheimer's disease.

Gentier RJ, Verheijen BM, Zamboni M, Stroeken MM, Hermes DJ, Küsters B, Steinbusch HW, Hopkins DA, Van Leeuwen FW - Front Neuroanat (2015)

Bottom Line: Mutations in ubiquitin B mRNA that result in UBB(+1) dose-dependently cause an impaired UPS, subsequent accumulation of UBB(+1) and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles.UBB(+1) distribution was compared with established probes for pre-tangles and tangles and Aβ plaques.UBB(+1) distribution found in line 3413 is partly mirrored in the AD brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University Maastricht, Netherlands.

ABSTRACT
Loss of protein quality control by the ubiquitin-proteasome system (UPS) during aging is one of the processes putatively contributing to cellular stress and Alzheimer's disease (AD) pathogenesis. Recently, pooled Genome Wide Association Studies (GWAS), pathway analysis and proteomics identified protein ubiquitination as one of the key modulators of AD. Mutations in ubiquitin B mRNA that result in UBB(+1) dose-dependently cause an impaired UPS, subsequent accumulation of UBB(+1) and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles. We used specific immunohistochemical probes for a comprehensive topographic mapping of the UBB(+1) distribution in the brains of transgenic mouse line 3413 overexpressing UBB(+1). We also mapped the expression of UBB(+1) in brain areas of AD patients selected based upon the distribution of UBB(+1) in line 3413. Therefore, we focused on the olfactory bulb, basal ganglia, nucleus basalis of Meynert, inferior colliculus and raphe nuclei. UBB(+1) distribution was compared with established probes for pre-tangles and tangles and Aβ plaques. UBB(+1) distribution found in line 3413 is partly mirrored in the AD brain. Specifically, nuclei with substantial accumulations of tangle-bearing neurons, such as the nucleus basalis of Meynert and raphe nuclei also present high densities of UBB(+1) positive tangles. Line 3413 is useful for studying the contribution of proteasomal dysfunction in AD. The findings are consistent with evidence that areas outside the forebrain are also affected in AD. Line 3413 may also be predictive for other conformational diseases, including related tauopathies and polyglutamine diseases, in which UBB(+1) accumulates in their cellular hallmarks.

No MeSH data available.


Related in: MedlinePlus

Photomicrographs of UBB+1 distribution in the brain of UBB+1 tg mice (line 3413) shown in sagittal and coronal sections. (A) Sagittal overview of UBB+1 staining in a 7-month-old 3413 tg mouse corresponding to sagittal figure 106 in the mouse brain atlas of Franklin and Paxinos (2007) with rectangles showing the locations of higher magnifications in (B–D). (B) OB, (C) Acb and (D) IC. (B) Shows the presence of UBB+1 in neurons of the OB, accessory olfactory bulb (AOB) and the anterior olfactory area (AO) at higher magnification. The insert shows a higher magnification of the AOB. (C) UBB+1 expression in the Acb. Insert shows higher magnification of UBB+1-positive cells. Filled triangle shows a cell in which the UBB+1 staining is cytoplasmic and the nucleus is negative. (D) UBB+1-immunoreactivity in the IC. Insert shows a higher magnification of the immunoreactive cells in the DCIC. (E) Coronal section of a 15-month-old 3413 tg mouse showing the presence of UBB+1 in the dorsal raphe (corresponding to coronal figure 69 in the mouse brain atlas of Franklin and Paxinos, 2007). (F) shows this region at a higher magnification. Insert in (F) shows the UBB+1-immunoreactive cells in the DR. Bars: (A), 1 mm; (B,D,F), 200 μm, (insert in B,C), 100 μm, (E), 500 μm, (insert in C, insert in D), 20 μm, insert in (F), 50 μm. Acb, nucleus accumbens; AOB, accessory olfactory bulb; AO, anterior olfactory area; Cb, cerebellum; CIC, central nucleus of IC; Cx, cerebral cortex; DCIC, dorsal cortex of IC; DR, dorsal raphe; EplA, external plexiform layer of the accessory olfactory bulb, ECIC, external cortex of IC; GlA, glomerular layer of the accessory olfactory bulb; Hip, hippocampus; IC, inferior colliculus; LS, lateral septal nucleus; LV, lateral ventricle; MiA, mitral cell layer of the accessory olfactory bulb; OB, olfactory bulb; PAG, periaqueductal gray; Sol, nucleus of the tractus solitarius; Tu, olfactory tubercle.
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Figure 1: Photomicrographs of UBB+1 distribution in the brain of UBB+1 tg mice (line 3413) shown in sagittal and coronal sections. (A) Sagittal overview of UBB+1 staining in a 7-month-old 3413 tg mouse corresponding to sagittal figure 106 in the mouse brain atlas of Franklin and Paxinos (2007) with rectangles showing the locations of higher magnifications in (B–D). (B) OB, (C) Acb and (D) IC. (B) Shows the presence of UBB+1 in neurons of the OB, accessory olfactory bulb (AOB) and the anterior olfactory area (AO) at higher magnification. The insert shows a higher magnification of the AOB. (C) UBB+1 expression in the Acb. Insert shows higher magnification of UBB+1-positive cells. Filled triangle shows a cell in which the UBB+1 staining is cytoplasmic and the nucleus is negative. (D) UBB+1-immunoreactivity in the IC. Insert shows a higher magnification of the immunoreactive cells in the DCIC. (E) Coronal section of a 15-month-old 3413 tg mouse showing the presence of UBB+1 in the dorsal raphe (corresponding to coronal figure 69 in the mouse brain atlas of Franklin and Paxinos, 2007). (F) shows this region at a higher magnification. Insert in (F) shows the UBB+1-immunoreactive cells in the DR. Bars: (A), 1 mm; (B,D,F), 200 μm, (insert in B,C), 100 μm, (E), 500 μm, (insert in C, insert in D), 20 μm, insert in (F), 50 μm. Acb, nucleus accumbens; AOB, accessory olfactory bulb; AO, anterior olfactory area; Cb, cerebellum; CIC, central nucleus of IC; Cx, cerebral cortex; DCIC, dorsal cortex of IC; DR, dorsal raphe; EplA, external plexiform layer of the accessory olfactory bulb, ECIC, external cortex of IC; GlA, glomerular layer of the accessory olfactory bulb; Hip, hippocampus; IC, inferior colliculus; LS, lateral septal nucleus; LV, lateral ventricle; MiA, mitral cell layer of the accessory olfactory bulb; OB, olfactory bulb; PAG, periaqueductal gray; Sol, nucleus of the tractus solitarius; Tu, olfactory tubercle.

Mentions: The present study extends and provides specific details in follow up to our initial global descriptions of UBB+1 expression in the forebrain (e.g., cerebral cortex, hippocampus, dentate gyrus, amygdala, and striatum) and the brainstem in the 3413 tg mice (Fischer et al., 2009; Irmler et al., 2012) (Figures 1, 2, Table 2). The CaMKIIα promoter mainly results in strong protein expression in forebrain areas (Mayford et al., 1996a). In keeping with this, the expression of UBB+1 protein was strong in the forebrain. In addition, after extensive mapping we observed a wide range of UBB+1 expression in hindbrain regions (e.g., brainstem and cerebellum) where other groups also showed the presence of CamKIIα (Mayford et al., 1996b). The analysis of the immunohistochemical expression in the mouse brain is aggregated by anatomical region (i.e., telencephalon, diencephalon, mesencephalon, pons, medulla oblongata, and cerebellum).


Localization of mutant ubiquitin in the brain of a transgenic mouse line with proteasomal inhibition and its validation at specific sites in Alzheimer's disease.

Gentier RJ, Verheijen BM, Zamboni M, Stroeken MM, Hermes DJ, Küsters B, Steinbusch HW, Hopkins DA, Van Leeuwen FW - Front Neuroanat (2015)

Photomicrographs of UBB+1 distribution in the brain of UBB+1 tg mice (line 3413) shown in sagittal and coronal sections. (A) Sagittal overview of UBB+1 staining in a 7-month-old 3413 tg mouse corresponding to sagittal figure 106 in the mouse brain atlas of Franklin and Paxinos (2007) with rectangles showing the locations of higher magnifications in (B–D). (B) OB, (C) Acb and (D) IC. (B) Shows the presence of UBB+1 in neurons of the OB, accessory olfactory bulb (AOB) and the anterior olfactory area (AO) at higher magnification. The insert shows a higher magnification of the AOB. (C) UBB+1 expression in the Acb. Insert shows higher magnification of UBB+1-positive cells. Filled triangle shows a cell in which the UBB+1 staining is cytoplasmic and the nucleus is negative. (D) UBB+1-immunoreactivity in the IC. Insert shows a higher magnification of the immunoreactive cells in the DCIC. (E) Coronal section of a 15-month-old 3413 tg mouse showing the presence of UBB+1 in the dorsal raphe (corresponding to coronal figure 69 in the mouse brain atlas of Franklin and Paxinos, 2007). (F) shows this region at a higher magnification. Insert in (F) shows the UBB+1-immunoreactive cells in the DR. Bars: (A), 1 mm; (B,D,F), 200 μm, (insert in B,C), 100 μm, (E), 500 μm, (insert in C, insert in D), 20 μm, insert in (F), 50 μm. Acb, nucleus accumbens; AOB, accessory olfactory bulb; AO, anterior olfactory area; Cb, cerebellum; CIC, central nucleus of IC; Cx, cerebral cortex; DCIC, dorsal cortex of IC; DR, dorsal raphe; EplA, external plexiform layer of the accessory olfactory bulb, ECIC, external cortex of IC; GlA, glomerular layer of the accessory olfactory bulb; Hip, hippocampus; IC, inferior colliculus; LS, lateral septal nucleus; LV, lateral ventricle; MiA, mitral cell layer of the accessory olfactory bulb; OB, olfactory bulb; PAG, periaqueductal gray; Sol, nucleus of the tractus solitarius; Tu, olfactory tubercle.
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Related In: Results  -  Collection

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Figure 1: Photomicrographs of UBB+1 distribution in the brain of UBB+1 tg mice (line 3413) shown in sagittal and coronal sections. (A) Sagittal overview of UBB+1 staining in a 7-month-old 3413 tg mouse corresponding to sagittal figure 106 in the mouse brain atlas of Franklin and Paxinos (2007) with rectangles showing the locations of higher magnifications in (B–D). (B) OB, (C) Acb and (D) IC. (B) Shows the presence of UBB+1 in neurons of the OB, accessory olfactory bulb (AOB) and the anterior olfactory area (AO) at higher magnification. The insert shows a higher magnification of the AOB. (C) UBB+1 expression in the Acb. Insert shows higher magnification of UBB+1-positive cells. Filled triangle shows a cell in which the UBB+1 staining is cytoplasmic and the nucleus is negative. (D) UBB+1-immunoreactivity in the IC. Insert shows a higher magnification of the immunoreactive cells in the DCIC. (E) Coronal section of a 15-month-old 3413 tg mouse showing the presence of UBB+1 in the dorsal raphe (corresponding to coronal figure 69 in the mouse brain atlas of Franklin and Paxinos, 2007). (F) shows this region at a higher magnification. Insert in (F) shows the UBB+1-immunoreactive cells in the DR. Bars: (A), 1 mm; (B,D,F), 200 μm, (insert in B,C), 100 μm, (E), 500 μm, (insert in C, insert in D), 20 μm, insert in (F), 50 μm. Acb, nucleus accumbens; AOB, accessory olfactory bulb; AO, anterior olfactory area; Cb, cerebellum; CIC, central nucleus of IC; Cx, cerebral cortex; DCIC, dorsal cortex of IC; DR, dorsal raphe; EplA, external plexiform layer of the accessory olfactory bulb, ECIC, external cortex of IC; GlA, glomerular layer of the accessory olfactory bulb; Hip, hippocampus; IC, inferior colliculus; LS, lateral septal nucleus; LV, lateral ventricle; MiA, mitral cell layer of the accessory olfactory bulb; OB, olfactory bulb; PAG, periaqueductal gray; Sol, nucleus of the tractus solitarius; Tu, olfactory tubercle.
Mentions: The present study extends and provides specific details in follow up to our initial global descriptions of UBB+1 expression in the forebrain (e.g., cerebral cortex, hippocampus, dentate gyrus, amygdala, and striatum) and the brainstem in the 3413 tg mice (Fischer et al., 2009; Irmler et al., 2012) (Figures 1, 2, Table 2). The CaMKIIα promoter mainly results in strong protein expression in forebrain areas (Mayford et al., 1996a). In keeping with this, the expression of UBB+1 protein was strong in the forebrain. In addition, after extensive mapping we observed a wide range of UBB+1 expression in hindbrain regions (e.g., brainstem and cerebellum) where other groups also showed the presence of CamKIIα (Mayford et al., 1996b). The analysis of the immunohistochemical expression in the mouse brain is aggregated by anatomical region (i.e., telencephalon, diencephalon, mesencephalon, pons, medulla oblongata, and cerebellum).

Bottom Line: Mutations in ubiquitin B mRNA that result in UBB(+1) dose-dependently cause an impaired UPS, subsequent accumulation of UBB(+1) and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles.UBB(+1) distribution was compared with established probes for pre-tangles and tangles and Aβ plaques.UBB(+1) distribution found in line 3413 is partly mirrored in the AD brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University Maastricht, Netherlands.

ABSTRACT
Loss of protein quality control by the ubiquitin-proteasome system (UPS) during aging is one of the processes putatively contributing to cellular stress and Alzheimer's disease (AD) pathogenesis. Recently, pooled Genome Wide Association Studies (GWAS), pathway analysis and proteomics identified protein ubiquitination as one of the key modulators of AD. Mutations in ubiquitin B mRNA that result in UBB(+1) dose-dependently cause an impaired UPS, subsequent accumulation of UBB(+1) and most probably depositions of other aberrant proteins present in plaques and neurofibrillary tangles. We used specific immunohistochemical probes for a comprehensive topographic mapping of the UBB(+1) distribution in the brains of transgenic mouse line 3413 overexpressing UBB(+1). We also mapped the expression of UBB(+1) in brain areas of AD patients selected based upon the distribution of UBB(+1) in line 3413. Therefore, we focused on the olfactory bulb, basal ganglia, nucleus basalis of Meynert, inferior colliculus and raphe nuclei. UBB(+1) distribution was compared with established probes for pre-tangles and tangles and Aβ plaques. UBB(+1) distribution found in line 3413 is partly mirrored in the AD brain. Specifically, nuclei with substantial accumulations of tangle-bearing neurons, such as the nucleus basalis of Meynert and raphe nuclei also present high densities of UBB(+1) positive tangles. Line 3413 is useful for studying the contribution of proteasomal dysfunction in AD. The findings are consistent with evidence that areas outside the forebrain are also affected in AD. Line 3413 may also be predictive for other conformational diseases, including related tauopathies and polyglutamine diseases, in which UBB(+1) accumulates in their cellular hallmarks.

No MeSH data available.


Related in: MedlinePlus