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.
| Original language | English |
|---|---|
| Article number | e1296 |
| Journal | Cell Death and Disease |
| Volume | 5 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2014 |
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ASJC Scopus subject areas
- Cell Biology
- Immunology
- Cancer Research
- Cellular and Molecular Neuroscience
- Medicine(all)
Cite this
Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models : Pharmacological characterization of SIRT1 and SIRT2 pathways. / Valle, C.; Salvatori, I.; Gerbino, V.; Rossi, S.; Palamiuc, L.; René, F.; Carrì, M. T.
In: Cell Death and Disease, Vol. 5, No. 6, e1296, 2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models
T2 - Pharmacological characterization of SIRT1 and SIRT2 pathways
AU - Valle, C.
AU - Salvatori, I.
AU - Gerbino, V.
AU - Rossi, S.
AU - Palamiuc, L.
AU - René, F.
AU - Carrì, M. T.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84903792981&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903792981&partnerID=8YFLogxK
U2 - 10.1038/cddis.2014.247
DO - 10.1038/cddis.2014.247
M3 - Article
C2 - 24946089
AN - SCOPUS:84903792981
VL - 5
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 6
M1 - e1296
ER -