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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

UBB+1 and AD neuropathology (NFTs, NTs, and Aβ plaques) in the human raphe nuclei. (A) Photomicrograph of a 50 μm-thick section from the brainstem cut perpendicular to the long axis of the spinal cord of patient #8 (Braak 5). (B–E) Higher magnifications of the MnR [lower boxed region in (A)] incubated with four antibodies against (B) UBB+1, (C) pre-tangles material (MC1), (D) tangles (CP13), and (E) Aβ plaques. (F–I) Larger magnifications of the DR [upper boxed region in (a)] incubated with the same four antibodies. (F) Ubi2A; (G) MC1; (H) CP13; (I) 6F3D. The raphe nuclei located in the rostral brainstem (MnR and DR) express selective vulnerability to tau pathology (asterisk, neuronal staining; filled triangle, NTs), being almost devoid of plaques (arrow). Both MnR and DR are strongly stained by antibodies directed against pre-tangle material (MC1) and NFTs (CP13), and present a moderate number of UBB+1-positive substrates (asterisk). Bars: (A), 1 mm, (B–I), 200 μm. Aq, cerebral aqueduct; DR, dorsal raphe nucleus; LC, locus coeruleus; mlf, medal longitudinal fasciculus; MnR, median raphe nucleus, PnO, pontine reticular nucleus oral part.
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Figure 8: UBB+1 and AD neuropathology (NFTs, NTs, and Aβ plaques) in the human raphe nuclei. (A) Photomicrograph of a 50 μm-thick section from the brainstem cut perpendicular to the long axis of the spinal cord of patient #8 (Braak 5). (B–E) Higher magnifications of the MnR [lower boxed region in (A)] incubated with four antibodies against (B) UBB+1, (C) pre-tangles material (MC1), (D) tangles (CP13), and (E) Aβ plaques. (F–I) Larger magnifications of the DR [upper boxed region in (a)] incubated with the same four antibodies. (F) Ubi2A; (G) MC1; (H) CP13; (I) 6F3D. The raphe nuclei located in the rostral brainstem (MnR and DR) express selective vulnerability to tau pathology (asterisk, neuronal staining; filled triangle, NTs), being almost devoid of plaques (arrow). Both MnR and DR are strongly stained by antibodies directed against pre-tangle material (MC1) and NFTs (CP13), and present a moderate number of UBB+1-positive substrates (asterisk). Bars: (A), 1 mm, (B–I), 200 μm. Aq, cerebral aqueduct; DR, dorsal raphe nucleus; LC, locus coeruleus; mlf, medal longitudinal fasciculus; MnR, median raphe nucleus, PnO, pontine reticular nucleus oral part.

Mentions: The subdivisions of the DR, namely dorsal DRD, DRV, DRVL, and DRI were equally affected by AD-related pathology with a moderate number of UBB+1 positive structures and high number of tangles. In the MnR, immunoreactive substrates, such as NFTs and NTs, were especially concentrated in the medial division (mMnR), while the PMnR exhibited AD-related pathology to a lesser extent (only expressing NTs, but not NFTs). Results are summarized in Table 5 and Figure 8.


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)

UBB+1 and AD neuropathology (NFTs, NTs, and Aβ plaques) in the human raphe nuclei. (A) Photomicrograph of a 50 μm-thick section from the brainstem cut perpendicular to the long axis of the spinal cord of patient #8 (Braak 5). (B–E) Higher magnifications of the MnR [lower boxed region in (A)] incubated with four antibodies against (B) UBB+1, (C) pre-tangles material (MC1), (D) tangles (CP13), and (E) Aβ plaques. (F–I) Larger magnifications of the DR [upper boxed region in (a)] incubated with the same four antibodies. (F) Ubi2A; (G) MC1; (H) CP13; (I) 6F3D. The raphe nuclei located in the rostral brainstem (MnR and DR) express selective vulnerability to tau pathology (asterisk, neuronal staining; filled triangle, NTs), being almost devoid of plaques (arrow). Both MnR and DR are strongly stained by antibodies directed against pre-tangle material (MC1) and NFTs (CP13), and present a moderate number of UBB+1-positive substrates (asterisk). Bars: (A), 1 mm, (B–I), 200 μm. Aq, cerebral aqueduct; DR, dorsal raphe nucleus; LC, locus coeruleus; mlf, medal longitudinal fasciculus; MnR, median raphe nucleus, PnO, pontine reticular nucleus oral part.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 8: UBB+1 and AD neuropathology (NFTs, NTs, and Aβ plaques) in the human raphe nuclei. (A) Photomicrograph of a 50 μm-thick section from the brainstem cut perpendicular to the long axis of the spinal cord of patient #8 (Braak 5). (B–E) Higher magnifications of the MnR [lower boxed region in (A)] incubated with four antibodies against (B) UBB+1, (C) pre-tangles material (MC1), (D) tangles (CP13), and (E) Aβ plaques. (F–I) Larger magnifications of the DR [upper boxed region in (a)] incubated with the same four antibodies. (F) Ubi2A; (G) MC1; (H) CP13; (I) 6F3D. The raphe nuclei located in the rostral brainstem (MnR and DR) express selective vulnerability to tau pathology (asterisk, neuronal staining; filled triangle, NTs), being almost devoid of plaques (arrow). Both MnR and DR are strongly stained by antibodies directed against pre-tangle material (MC1) and NFTs (CP13), and present a moderate number of UBB+1-positive substrates (asterisk). Bars: (A), 1 mm, (B–I), 200 μm. Aq, cerebral aqueduct; DR, dorsal raphe nucleus; LC, locus coeruleus; mlf, medal longitudinal fasciculus; MnR, median raphe nucleus, PnO, pontine reticular nucleus oral part.
Mentions: The subdivisions of the DR, namely dorsal DRD, DRV, DRVL, and DRI were equally affected by AD-related pathology with a moderate number of UBB+1 positive structures and high number of tangles. In the MnR, immunoreactive substrates, such as NFTs and NTs, were especially concentrated in the medial division (mMnR), while the PMnR exhibited AD-related pathology to a lesser extent (only expressing NTs, but not NFTs). Results are summarized in Table 5 and Figure 8.

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