Article (Scientific journals)
Mitochondrial Defects and Neurodegeneration in Mice Overexpressing Wild Type or G399S Mutant HtrA2
Casadei, Nicolas; Sood, Poonan; Ulrich, Thomas et al.
2016In Human Molecular Genetics, 25 (3), p. 459-71
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Keywords :
HtrA2; Parkinson's disease; Mitochondria; Mouse model; bioinformatics; protein structure analysis
Abstract :
[en] The protease HtrA2 has a protective role inside mitochondria, but promotes apoptosis under stress. We previously identified the G399S HtrA2 mutation in Parkinson's disease (PD) patients and reported mitochondrial dysfunction in vitro. Mitochondrial dysfunction is a common feature of PD and related to neurodegeneration. Complete loss of HtrA2 has been shown to cause neurodegeneration in mice. However, the full impact of HtrA2 overexpression or the G399S mutation is still to be determined in vivo. Here, we report the first HtrA2 G399S transgenic mouse model. Our data suggest that the mutation has a dominant-negative effect. We also describe a toxic effect of wild-type (WT) HtrA2 overexpression. Only low overexpression of the G399S mutation allowed viable animals and we suggest that the mutant protein is likely unstable. This is accompanied by reduced mitochondrial respiratory capacity and sensitivity to apoptotic cell death. Mice overexpressing WT HtrA2 were viable, yet these animals have inhibited mitochondrial respiration and significant induction of apoptosis in the brain leading to motor dysfunction, highlighting the opposing roles of HtrA2. Our data further underscore the importance of HtrA2 as a key mediator of mitochondrial function and its fine regulatory role in cell fate. The location and abundance of HtrA2 is tightly controlled and, therefore, human mutations leading to gain- or loss of function could provide significant risk for PD-related neurodegeneration.
Research center :
ULHPC - University of Luxembourg: High Performance Computing
- Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Disciplines :
Physical, chemical, mathematical & earth Sciences: Multidisciplinary, general & others
Genetics & genetic processes
Author, co-author :
Casadei, Nicolas
Sood, Poonan
Ulrich, Thomas
Kieper, Nicole
Helling, Stefan
May, Caroline
GLAAB, Enrico  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Chen, Jing
Nuber, Silke
Marcus, Katrin
Rapaport, Doron
Ott, Thomas
Riess, O.
KRÜGER, Rejko ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Fitzgerald, Julia
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Title :
Mitochondrial Defects and Neurodegeneration in Mice Overexpressing Wild Type or G399S Mutant HtrA2
Publication date :
Journal title :
Human Molecular Genetics
Publisher :
Oxford University Press, Oxford, United Kingdom
Volume :
Issue :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
FnR Project :
FNR5782168 - Exploring Parkinson'S Disease Inhibitor Efficacy On A Non-dopaminergic Target, 2013 (01/12/2013-31/05/2016) - Enrico Glaab
Commentary :
(c) The Author 2015. Published by Oxford University Press. All rights reserved.
Available on ORBilu :
since 23 November 2015


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