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Updated: Apr 28, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological
C Valle1, I Salvatori2, V Gerbino2
11] Institute for Cell Biology and Neurobiology, CNR, Rome, Italy [2] Fondazione Santa Lucia IRCCS, Rome, Italy.
Abstract:
Acetylation homeostasis is thought to play a role in amyotrophic lateral sclerosis, and treatment with inhibitors of histone deacetylases has been considered a potential and attractive therapeutic approach, despite the lack of a thorough study of this class of proteins. In this study, we have considerably extended previous knowledge on the expression of 13 histone deacetylases in tissues (spinal cord and muscle) from mice carrying two different ALS-linked SOD1 mutations (G93A-SOD1 and G86R-SOD1). We have then focused on class III histone deacetylases SIRT1 and SIRT2 that are considered relevant in neurodegenerative diseases. SIRT1 decreases in the spinal cord, but increases in muscle during the progression of the disease, and a similar expression pattern is observed in the corresponding cell models (neuroblastoma and myoblasts). SIRT2 mRNA expression increases in the spinal cord in both G93A-SOD1 and G86R-SOD1 mice but protein expression is substantially unchanged in all the models examined. At variance with other sirtuin modulators (sirtinol, AGK2 and SRT1720), the well-known SIRT1 inhibitor Ex527 has positive effects on survival of neuronal cells expressing mutant SOD1, but this effect is neither mediated by SIRT1 inhibition nor by SIRT2 inhibition. These data call for caution in proposing sirtuin modulation as a target for treatment.
Insights
Histone deacetylase (HDAC) inhibitors are explored for amyotrophic lateral sclerosis (ALS). This study reveals complex changes in SIRT1 and SIRT2 in ALS mouse models, suggesting caution for sirtuin-targeted therapies.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Acetylation homeostasis is implicated in amyotrophic lateral sclerosis (ALS).
- Histone deacetylase (HDAC) inhibitors are a potential therapeutic avenue for ALS.
- Previous studies on HDAC expression in ALS are limited.
Purpose of the Study:
- To investigate the expression of 13 HDACs in spinal cord and muscle of ALS mouse models.
- To focus on class III HDACs, SIRT1 and SIRT2, in neurodegenerative disease contexts.
- To evaluate the therapeutic potential of targeting sirtuins in ALS.
Main Methods:
- Analysis of HDAC expression in G93A-SOD1 and G86R-SOD1 mutant mice.
- Examination of SIRT1 and SIRT2 expression in spinal cord, muscle, neuroblastoma, and myoblast cell models.
- Assessment of the effects of the SIRT1 inhibitor Ex527 on neuronal cell survival.
Main Results:
- SIRT1 expression decreased in the spinal cord but increased in muscle during ALS progression.
- SIRT2 mRNA increased in the spinal cord, but protein levels remained unchanged across models.
- Ex527 improved neuronal survival in mutant SOD1 cells, independent of SIRT1 or SIRT2 inhibition.
Conclusions:
- SIRT1 and SIRT2 exhibit distinct expression patterns in ALS mouse models and cell lines.
- The observed effects of Ex527 suggest its neuroprotective role is not mediated by direct SIRT1 or SIRT2 inhibition.
- Targeting sirtuins for ALS treatment requires further investigation and caution.
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