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.
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.
Helmholtz Zentrum München, National Research Center for Environment and Health, GmbH, Institute of Experimental Genetics, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
Martin
M
Irmler
Romina J G
RJ
Gentier
Frank J A
FJ
Dennissen
Holger
H
Schulz
Ines
I
Bolle
Sabine M
SM
Hölter
Magdalena
M
Kallnik
Jing Jun
JJ
Cheng
Martin
M
Klingenspor
Jan
J
Rozman
Nicole
N
Ehrhardt
Denise J H P
DJ
Hermes
Valérie
V
Gailus-Durner
Helmut
H
Fuchs
Martin
M
Hrabě de Angelis
Helmut E
HE
Meyer
David A
DA
Hopkins
Fred W
FW
Van Leeuwen
Johannes
J
Beckers
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D012119:Respiration; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism
C527284:Ubb protein, mouse; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex