Abstract
Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired.
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Abbreviations
- AD:
-
Alzheimer’s disease
- AMN:
-
adrenomyeloneuropathy
- APP:
-
amyloid precursor protein
- ATP:
-
adenosine triphosphate
- C26:0:
-
hexacosanoic acid
- CCALD:
-
childhood cerebral adrenoleukodystrophy
- CAMN:
-
cerebral adrenomyeloneuropathy
- CTL:
-
control
- ETC:
-
electron transport chain
- FOXO1:
-
forkhead box protein O1
- GFAP:
-
glial fibrillary acidic protein
- GR:
-
glutathione reductase
- GSH:
-
reduced glutathione
- GSSG:
-
glutathione disulfide
- HD:
-
Huntington’s disease
- HSP:
-
Hereditary Spastic Paraplegia
- MDA:
-
malondialdehyde
- mPTP:
-
mitochondrial permeability transition pore
- mtDNA:
-
mitochondrial DNA
- NAD+:
-
nicotinamide adenine dinucleotide (oxidized form)
- NADH:
-
nicotinamide adenine dinucleotide (reduced form)
- NAM:
-
nicotinamide
- nDNA:
-
nuclear DNA
- NDUFB8:
-
NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, 19kDa
- NMAT1:
-
nicotinamide mononucleotide adenylyl transferase1
- NRF-1:
-
nuclear respiratory factor-1
- NRF-2:
-
nuclear respiratory factor-2
- OXPHOS:
-
oxidative phosphorylation
- PD:
-
Parkinson’s disease
- PGC-1α:
-
peroxisome proliferator-activated receptor gamma coactivators-1 alpha
- PK:
-
pyruvate kinase
- ROS:
-
reactive oxygen species
- RSV:
-
resveratrol
- RT-PCR:
-
real time PCR
- SDHB:
-
succinate dehydrogenase complex, subunit B, iron sulfur (Ip)
- SIRT1:
-
sirtuin 1
- SMI32:
-
neurofilament H non-phosphorylated
- SPG7:
-
spastic paraplegia 7
- TFAM:
-
mitochondrial transcription factor A
- VDAC1:
-
voltage-dependent anion channel 1
- VLCFA:
-
very long-chain fatty acids
- Wlds:
-
Wallerian degeneration slow
- X-ALD:
-
X-linked adrenoleukodystrophy
- WT:
-
wild type
- ΔΨm:
-
inner mitochondrial membrane potential
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Acknowledgements
This work was supported by grants from the European Commission [FP7-241622], the Spanish Institute for Health Carlos III [FIS PI11/01043], the Oliver’s Army Foundation, the Government of Catalonia [2009SGR85 to AP], the Spanish Institute for Health Carlos III [Miguel Servet program CP11/00080 to S.F.], the European Leukodystrophy Association (ELA) [ELA 2010-020F1 to SF, ELA 2013-003F1 to LM], the Spanish Ministry of Education [FPU program AP2008-03728 to LM]. JG held an IDIBELL PhD fellowship. The studies conducted at the Experimental Medicine Department were supported in part by R+D grants from the Spanish Ministry of Science and Innovation [BFU2009-11879/BFI], the Spanish Ministry of Health [PI081843, PI1300584], the Government of Catalonia [2009SGR735], the 'La Caixa' Foundation and COST B35 Action of the European Union. CIBERER and CIBERNED are initiatives of the Spanish Institute for Health Carlos III.
Author Contributions
LM, SF and AP participated in the study design. LM, MR, JG, CG and SF carried out all experimental assays except histopathological studies, performed by NYC and FB. MJ and AN performed GSH quantification and JB performed high-resolution respirometry. LM and AP wrote the manuscript. All authors reviewed the manuscript.
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Morató, L., Ruiz, M., Boada, J. et al. Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy. Cell Death Differ 22, 1742–1753 (2015). https://doi.org/10.1038/cdd.2015.20
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DOI: https://doi.org/10.1038/cdd.2015.20
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