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1.
Cell Death Dis ; 6: e1943, 2015 Oct 22.
Article in English | MEDLINE | ID: mdl-26492376

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to motor neuron loss. Fused in sarcoma (FUS) protein carrying ALS-associated mutations localizes to stress granules and causes their coalescence into larger aggregates. Here we show that Pur-alpha physically interacts with mutated FUS in an RNA-dependent manner. Pur-alpha colocalizes with FUS carrying mutations in stress granules of motoneuronal cells differentiated from induced pluripotent stem cells and that are derived from ALS patients. We observe that both Pur-alpha and mutated FUS upregulate phosphorylation of the translation initiation factor eukaryotic translation initiation factor 2 alpha and consistently inhibit global protein synthesis. In vivo expression of Pur-alpha in different Drosophila tissues significatively exacerbates the neurodegeneration caused by mutated FUS. Conversely, the downregulation of Pur-alpha in neurons expressing mutated FUS significatively improves fly climbing activity. All these findings suggest that Pur-alpha, through the control of mRNA translation, might be involved in the pathogenesis of ALS associated with the mutation of FUS, and that an alteration of protein synthesis may be directly implicated in the disease. Finally, in vivo RNAi-mediated ablation of Pur-alpha produced locomotion defects in Drosophila, indicating a pivotal role for this protein in the motoneuronal function.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , DNA-Binding Proteins/physiology , Drosophila Proteins/physiology , Nerve Tissue Proteins/physiology , RNA-Binding Protein FUS/physiology , Transcription Factors/physiology , Amyotrophic Lateral Sclerosis/pathology , Animals , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Drosophila/genetics , Drosophila/physiology , Drosophila Proteins/antagonists & inhibitors , Drosophila Proteins/genetics , Eukaryotic Initiation Factor-2/metabolism , HeLa Cells , Humans , Induced Pluripotent Stem Cells , Motor Neurons/metabolism , Mutation , Nerve Tissue Proteins/metabolism , Phosphorylation , Protein Biosynthesis/genetics , RNA Interference , RNA, Messenger/metabolism , RNA-Binding Protein FUS/genetics , RNA-Binding Protein FUS/metabolism , Ribosomes/metabolism , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Transcription Factors/metabolism
2.
Cell Death Dis ; 5: e1296, 2014 Jun 19.
Article in English | MEDLINE | ID: mdl-24946089

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.


Subject(s)
Amyotrophic Lateral Sclerosis/enzymology , Histone Deacetylases/metabolism , Sirtuin 1/metabolism , Sirtuin 2/metabolism , Amino Acid Substitution , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Animals , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Histone Deacetylases/genetics , Humans , Mice , Mice, Transgenic , Mutation, Missense , Sirtuin 1/antagonists & inhibitors , Sirtuin 1/genetics , Sirtuin 2/antagonists & inhibitors , Sirtuin 2/genetics , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase-1
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