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Long-term proteasomal inhibition in transgenic mice by UBB(+1) expression results in dysfunction of central respiration control reminiscent of brainstem neuropathology in Alzheimer patients.

Irmler M, Gentier RJ, Dennissen FJ, Schulz H, Bolle I, Hölter SM, Kallnik M, Cheng JJ, Klingenspor M, Rozman J, Ehrhardt N, Hermes DJ, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Meyer HE, Hopkins DA, Van Leeuwen FW, Beckers J - Acta Neuropathol. (2012)

Bottom Line: The resulting mutant protein has been shown to inhibit proteasome function.These regions included, e.g., the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nucleus.The UBB(+1) expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients.

View Article: PubMed Central - PubMed

Affiliation: Helmholtz Zentrum München, National Research Center for Environment and Health, GmbH, Institute of Experimental Genetics, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.

ABSTRACT
Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases, a mutant form of ubiquitin B (UBB(+1)) accumulates in disease-specific aggregates. UBB(+1) mRNA is generated at low levels in vivo during transcription from the ubiquitin B locus by molecular misreading. The resulting mutant protein has been shown to inhibit proteasome function. To elucidate causative effects and neuropathological consequences of UBB(+1) accumulation, we used a UBB(+1) expressing transgenic mouse line that models UPS inhibition in neurons and exhibits behavioral phenotypes reminiscent of Alzheimer's disease (AD). In order to reveal affected organs and functions, young and aged UBB(+1) transgenic mice were comprehensively phenotyped for more than 240 parameters. This revealed unexpected changes in spontaneous breathing patterns and an altered response to hypoxic conditions. Our findings point to a central dysfunction of respiratory regulation in transgenic mice in comparison to wild-type littermate mice. Accordingly, UBB(+1) was strongly expressed in brainstem regions of transgenic mice controlling respiration. These regions included, e.g., the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nucleus. In addition, UBB(+1) was also strongly expressed in these anatomical structures of AD patients (Braak stage #6) and was not expressed in non-demented controls. We conclude that long-term UPS inhibition due to UBB(+1) expression causes central breathing dysfunction in a transgenic mouse model of AD. The UBB(+1) expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients.

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UBB+1 tg spontaneous breathing patterns measured by whole body plethysmography. Male UBB+1 tg (black bars) and control mice (grey bars) at the age of a 3 months and b, c 12 months were analyzed (n = 6 for all groups). a Shows the respiratory rate (f), expiratory time (Te), and relative duration of inspiration (Ti/TT) for male mice under activity. b, c Show the mean expiratory flow rate (MEF), expiratory time (Te), and the relative duration of inspiration (Ti/TT) at the age of 12 months at rest and under activity, respectively. The mean values for the indicated parameters of the control group were set to 100 % and significance by Student’s t test is indicated by *p<0.05, **p<0.01, ***p < 0.001; error bars represent SEM
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Fig1: UBB+1 tg spontaneous breathing patterns measured by whole body plethysmography. Male UBB+1 tg (black bars) and control mice (grey bars) at the age of a 3 months and b, c 12 months were analyzed (n = 6 for all groups). a Shows the respiratory rate (f), expiratory time (Te), and relative duration of inspiration (Ti/TT) for male mice under activity. b, c Show the mean expiratory flow rate (MEF), expiratory time (Te), and the relative duration of inspiration (Ti/TT) at the age of 12 months at rest and under activity, respectively. The mean values for the indicated parameters of the control group were set to 100 % and significance by Student’s t test is indicated by *p<0.05, **p<0.01, ***p < 0.001; error bars represent SEM

Mentions: Spontaneous breathing patterns were measured at rest and at activity, i.e., during calm sitting and short periods of sleeping and while animals were exploring the test chamber, respectively. Data were analyzed for each gender separately. At 3 months of age, significant genotype-dependent respiration differences between control mice and UBB+1 tg mice were detected for male mice during activity. In this group, the respiratory rate in UBB+1 tg mice was 8 % higher mostly due to a shorter expiratory time (Fig. 1a; S4). In addition, a slightly increased relative duration of inspiration was also observed in male UBB+1 tg mice compared to wild-type control mice (6 % increase, p < 0.001). The spontaneous breathing of UBB+1 tg mice was even more affected at the age of 12 months when respiratory timing was significantly altered in male UBB+1 tg mice during activity and at rest (Fig. 1b, c). The trend towards longer time of expiration and shorter relative duration of inspiration during aging was consistent among UBB+1 tg males (Fig. 1b, c; Fig. S5) and females (Fig. S1, S5) in comparison to the respective wild-type control groups. At 12 months of age, male UBB+1 tg mice exhibited significantly shorter relative duration of inspiration at rest (90 ± 3 %, Fig. 1b) and during activity (94 ± 3 %, Fig. 1c) compared to male wild-type control mice (set to 100 %). Since the inspiratory time and the mean inspiratory flow rate were not significantly affected in male UBB+1 tg mice (Fig. S5), the observed shorter relative duration of inspiration values was primarily due to an elevated expiratory time. The mean expiratory flow rate was significantly lower at rest (83 ± 4 %) and activity (91 ± 4 %) in UBB+1 expressing tg mice compared to the corresponding male control group (set to 100 %), which is most likely due to the differences in the expiratory time (Fig. 1b, c). Thus, overall the spontaneous breathing pattern of male transgenic UBB+1 mice was affected by a statistically significant increase of the expiratory time over age. In contrast, the male wild-type control group had a tendency towards reduced expiratory time over age. Female transgenic mice at 12 months of age and male transgenic mice at 18 months of age showed similar trends, which became significant for the latter (p < 0.05; Fig. S1, S2). Absolute values for the spontaneous breathing parameters are provided in the supplementary figures S4, S5 and S6.Fig. 1


Long-term proteasomal inhibition in transgenic mice by UBB(+1) expression results in dysfunction of central respiration control reminiscent of brainstem neuropathology in Alzheimer patients.

Irmler M, Gentier RJ, Dennissen FJ, Schulz H, Bolle I, Hölter SM, Kallnik M, Cheng JJ, Klingenspor M, Rozman J, Ehrhardt N, Hermes DJ, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Meyer HE, Hopkins DA, Van Leeuwen FW, Beckers J - Acta Neuropathol. (2012)

UBB+1 tg spontaneous breathing patterns measured by whole body plethysmography. Male UBB+1 tg (black bars) and control mice (grey bars) at the age of a 3 months and b, c 12 months were analyzed (n = 6 for all groups). a Shows the respiratory rate (f), expiratory time (Te), and relative duration of inspiration (Ti/TT) for male mice under activity. b, c Show the mean expiratory flow rate (MEF), expiratory time (Te), and the relative duration of inspiration (Ti/TT) at the age of 12 months at rest and under activity, respectively. The mean values for the indicated parameters of the control group were set to 100 % and significance by Student’s t test is indicated by *p<0.05, **p<0.01, ***p < 0.001; error bars represent SEM
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3400757&req=5

Fig1: UBB+1 tg spontaneous breathing patterns measured by whole body plethysmography. Male UBB+1 tg (black bars) and control mice (grey bars) at the age of a 3 months and b, c 12 months were analyzed (n = 6 for all groups). a Shows the respiratory rate (f), expiratory time (Te), and relative duration of inspiration (Ti/TT) for male mice under activity. b, c Show the mean expiratory flow rate (MEF), expiratory time (Te), and the relative duration of inspiration (Ti/TT) at the age of 12 months at rest and under activity, respectively. The mean values for the indicated parameters of the control group were set to 100 % and significance by Student’s t test is indicated by *p<0.05, **p<0.01, ***p < 0.001; error bars represent SEM
Mentions: Spontaneous breathing patterns were measured at rest and at activity, i.e., during calm sitting and short periods of sleeping and while animals were exploring the test chamber, respectively. Data were analyzed for each gender separately. At 3 months of age, significant genotype-dependent respiration differences between control mice and UBB+1 tg mice were detected for male mice during activity. In this group, the respiratory rate in UBB+1 tg mice was 8 % higher mostly due to a shorter expiratory time (Fig. 1a; S4). In addition, a slightly increased relative duration of inspiration was also observed in male UBB+1 tg mice compared to wild-type control mice (6 % increase, p < 0.001). The spontaneous breathing of UBB+1 tg mice was even more affected at the age of 12 months when respiratory timing was significantly altered in male UBB+1 tg mice during activity and at rest (Fig. 1b, c). The trend towards longer time of expiration and shorter relative duration of inspiration during aging was consistent among UBB+1 tg males (Fig. 1b, c; Fig. S5) and females (Fig. S1, S5) in comparison to the respective wild-type control groups. At 12 months of age, male UBB+1 tg mice exhibited significantly shorter relative duration of inspiration at rest (90 ± 3 %, Fig. 1b) and during activity (94 ± 3 %, Fig. 1c) compared to male wild-type control mice (set to 100 %). Since the inspiratory time and the mean inspiratory flow rate were not significantly affected in male UBB+1 tg mice (Fig. S5), the observed shorter relative duration of inspiration values was primarily due to an elevated expiratory time. The mean expiratory flow rate was significantly lower at rest (83 ± 4 %) and activity (91 ± 4 %) in UBB+1 expressing tg mice compared to the corresponding male control group (set to 100 %), which is most likely due to the differences in the expiratory time (Fig. 1b, c). Thus, overall the spontaneous breathing pattern of male transgenic UBB+1 mice was affected by a statistically significant increase of the expiratory time over age. In contrast, the male wild-type control group had a tendency towards reduced expiratory time over age. Female transgenic mice at 12 months of age and male transgenic mice at 18 months of age showed similar trends, which became significant for the latter (p < 0.05; Fig. S1, S2). Absolute values for the spontaneous breathing parameters are provided in the supplementary figures S4, S5 and S6.Fig. 1

Bottom Line: The resulting mutant protein has been shown to inhibit proteasome function.These regions included, e.g., the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nucleus.The UBB(+1) expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients.

View Article: PubMed Central - PubMed

Affiliation: Helmholtz Zentrum München, National Research Center for Environment and Health, GmbH, Institute of Experimental Genetics, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.

ABSTRACT
Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases, a mutant form of ubiquitin B (UBB(+1)) accumulates in disease-specific aggregates. UBB(+1) mRNA is generated at low levels in vivo during transcription from the ubiquitin B locus by molecular misreading. The resulting mutant protein has been shown to inhibit proteasome function. To elucidate causative effects and neuropathological consequences of UBB(+1) accumulation, we used a UBB(+1) expressing transgenic mouse line that models UPS inhibition in neurons and exhibits behavioral phenotypes reminiscent of Alzheimer's disease (AD). In order to reveal affected organs and functions, young and aged UBB(+1) transgenic mice were comprehensively phenotyped for more than 240 parameters. This revealed unexpected changes in spontaneous breathing patterns and an altered response to hypoxic conditions. Our findings point to a central dysfunction of respiratory regulation in transgenic mice in comparison to wild-type littermate mice. Accordingly, UBB(+1) was strongly expressed in brainstem regions of transgenic mice controlling respiration. These regions included, e.g., the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nucleus. In addition, UBB(+1) was also strongly expressed in these anatomical structures of AD patients (Braak stage #6) and was not expressed in non-demented controls. We conclude that long-term UPS inhibition due to UBB(+1) expression causes central breathing dysfunction in a transgenic mouse model of AD. The UBB(+1) expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients.

Show MeSH
Related in: MedlinePlus