Idebenone and resveratrol extend lifespan and improve motor function of HtrA2 knockout mice.
Heterozygous loss-of-function mutation of the human gene for the mitochondrial protease HtrA2 has been associated with increased risk to develop mitochondrial dysfunction, a process known to contribute to neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). Knockout of HtrA2 in mice also leads to mitochondrial dysfunction and to phenotypes that resemble those found in neurodegenerative disorders and, ultimately, lead to death of animals around postnatal day 30. Here, we show that Idebenone, a synthetic antioxidant of the coenzyme Q family, and Resveratrol, a bioactive compound extracted from grapes, are both able to ameliorate this phenotype. Feeding HtrA2 knockout mice with either compound extends lifespan and delays worsening of the motor phenotype. Experiments conducted in cell culture and on brain tissue of mice revealed that each compound has a different mechanism of action. While Idebenone acts by downregulating the integrated stress response, Resveratrol acts by attenuating apoptosis at the level of Bax. These activities can account for the delay in neuronal degeneration in the striata of these mice and illustrate the potential of these compounds as effective therapeutic approaches against neurodegenerative disorders such as HD or PD.
Department of NeuroDegeneration and Restorative Research, DFG Research Center: Molecular Physiology of the Brain, University Medicine Göttingen, Georg-August University, Göttingen, Germany. egerhar1@gwdg.de
Ellen
E
Gerhardt
Simone
S
Gräber
Eva M
EM
Szego
Nicoleta
N
Moisoi
L Miguel
LM
Martins
Tiago F
TF
Outeiro
Pawel
P
Kermer
D000818:Animals; D002452:Cell Count; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D000074923:High-Temperature Requirement A Serine Peptidase 2; D008136:Longevity / Q000187:drug effects*; D051379:Mice; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics*; D009043:Motor Activity / Q000187:drug effects*; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D000077185:Resveratrol; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
C497250:Ddit3 protein, mouse; D024101:Mitochondrial Proteins; D013267:Stilbenes; D014451:Ubiquinone; D051742:Transcription Factor CHOP; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; C036619:idebenone; D000077185:Resveratrol