Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyotrophic lateral sclerosis (ALS) is characterized by motoneuron (MN) degeneration, generalized weakness, and muscle atrophy. The premature death of MNs is thought to be a determinant in the onset of this disease. In a transgenic mouse model of ALS expressing the G86R mutant superoxide dismutase 1 (mSOD1), we demonstrated previously that CREB (cAMP response element-binding protein)-binding protein (CBP) and histone acetylation levels were specifically decreased in nuclei of degenerating MNs. We show here that oxidative stress and mSOD1 overexpression can both impinge on CBP levels by transcriptional repression, in an MN-derived cell line. Histone deacetylase inhibitor (HDACi) treatment was able to reset proper acetylation levels and displayed an efficient neuroprotective capacity against oxidative stress in vitro. Interestingly, HDACi also upregulated CBP transcriptional expression in MNs. Moreover, when injected to G86R mice in vivo, the HDACi sodium valproate (VPA) maintained normal acetylation levels in the spinal cord, efficiently restored CBP levels in MNs, and significantly prevented MN death in these animals. However, despite neuroprotection, mean survival of treated animals was not significantly improved (<5%), and they died presenting the classical ALS symptoms. VPA was not able to prevent disruption of neuromuscular junctions, although it slightly delayed the onset of motor decline and retarded muscular atrophy to some extent. Together, these data show that neuroprotection can improve disease onset, but clearly provide evidence that one can uncouple MN survival from whole-animal survival and point to the neuromuscular junction perturbation as a primary event of ALS onset.
 ...
PMID:Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. 1752 99

Histone deacetylase (HDAC) inhibition as a therapeutic regimen in motor neuron diseases (MND) is generating intense interest in both the scientific and medical areas, with a number of potent compounds having demonstrated good safety profiles and hints of clinical activity on animal models. In this review, we discuss recent developments in dissecting the mechanism of action of HDAC inhibitors (HDACi) as a new group of mechanism-based drugs for motor neuron diseases, together with current progress in understanding their clinical application. We also discuss how the use of HDACi on animal models with motor neuron defects has allowed critical advances in the understanding of the pathophysiology of motor neuron diseases. The use of HDACi and possible mechanisms of action will be reviewed in three MND, i.e. amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA), diseases among which clinical trials with HDACi are currently perfomed (ALS, SMA).
 ...
PMID:Histone deacetylase inhibitors: therapeutic agents and research tools for deciphering motor neuron diseases. 1853 6

Histone deacetylases (HDACs) are important regulators of gene expression and cell differentiation. The HDAC inhibitors have recently been considered as potential novel neuroprotective drugs for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A major limitation, however, lies in the broad spectrum of action of currently available HDAC inhibitors that may cause a variety of toxic side effects. The mRNA expression levels of the HDAC isoforms HDACs 1 to 11 have previously been characterized in rat brain but have not been studied in human tissue. Using in situ hybridization histochemistry and immunohistochemistry we assessed the distribution and expression levels of HDACs 1to 11 in postmortem ALS and control brain and spinal cord specimens (n = 6 cases each) to determine alterations in the mRNA expression pattern that could provide a basis for disease-specific therapies. We found a reduction of HDAC 11 mRNA and increased HDAC 2 levels in ALS brain and spinal cord compared with controls. A more precise knowledge of the disease-related expression pattern could lead to the development of more specific pharmacotherapeutic approaches.
 ...
PMID:Differential histone deacetylase mRNA expression patterns in amyotrophic lateral sclerosis. 2046 34

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that primarily affects motor neurons in the brain and spinal cord. Histone deacetylase (HDAC) inhibitors have neuroprotective effects potentially useful for the treatment of neurodegenerative diseases including ALS; however, the molecular mechanisms underlying their potential efficacy is not well understood. Here we report that protein acetylation in urea-soluble proteins is differently regulated in post-mortem ALS spinal cord. Two-dimensional electrophoresis (2-DE) analysis reveals several protein clusters with similar molecular weight but different charge status. Liquid chromatography and tandem mass spectrometry (LC-MS/MS) identifies glial fibrillary acidic protein (GFAP) as the dominant component in the protein clusters. Further analysis indicates six heavily acetylated lysine residues at positions 89, 153, 189, 218, 259 and 331 of GFAP. Immunoprecipitation followed by Western blotting confirms that the larger form of GFAP fragments are acetylated and upregulated in ALS spinal cord. Further studies demonstrate that acetylation of the proteins additional to GFAP is differently regulated, suggesting that acetylation and/or deacetylation play an important role in pathogenesis of ALS.
...
PMID:Proteomic analysis reveals differentially regulated protein acetylation in human amyotrophic lateral sclerosis spinal cord. 2431 1