Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Huntington's disease can be used as a model to study neurodegenerative disorders caused by aggregation-prone proteins. It has been proposed that the entrapment of transcription factors in aggregates plays an important role in pathogenesis. We now report that the transcriptional activity of CBP is already repressed in the early time points by soluble mutant huntingtin, whereas the histone acetylase activity of CBP/p300 is gradually diminished over time. Mutant huntingtin bound much stronger to CBP than normal huntingtin, possibly contributing to repression. Especially at the later time points, CBP protein level was gradually reduced via the proteasome pathway. In sharp contrast, p300 was unaffected by mutant huntingtin. This selective degradation of CBP was absent in spinocerebellar ataxia 3. Thus, mutant huntingtin specifically affects CBP and not p300 both at the early and later time points, via multiple mechanisms. In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyltransferases may affect chromatin structure and transcription and thus contribute to neurodegeneration.
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PMID:Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. 1645 24

Spinocerebellar ataxia type 1 (SCA1) is an incurable neurodegenerative disease resulting from loss of Purkinje neurones within the cerebellum. The ubiquitin proteasome pathway (UPP) has been implicated in SCA1 but the role of proteolysis in the disease is still poorly understood. To further investigate this issue in vivo, genetic crosses were performed between an established mouse model of SCA1 and novel strains expressing elevated levels of wild type or mutant isoforms of ubiquitin. The K48R mutant isoform of ubiquitin (a dominant negative inhibitor of proteolysis) was found to significantly delay the deterioration of Purkinje neurones as evidenced by behavioural, morphological, and molecular indicators. This delay was accompanied by stabilization of p300/CBP, transcriptional mediators whose abundance and activity would otherwise decline in the course of the SCA1 disease, and persistence of protein kinase C gamma (PKCgamma), a protein involved in Purkinje cell dendritic development that is mutated in one form of spinocerebellar ataxia. Whereas the stabilization of p300/CBP was found to occur at the post-translational level the modulation of PKCgamma was at the level of transcription. These results are consistent with transcriptional dysregulation as a key mechanism in neurodegeneration through loss of p300/CBP. Further, the results suggest that the UPP is a potentially useful target for the development of novel therapies for the treatment of neurodegenerative disease.
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PMID:Delayed spinocerebellar ataxia in transgenic mice expressing mutant ubiquitin. 1640 51

Huntington's disease can be used as a model to study neurodegenerative disorders caused by aggregation-prone proteins. It has been proposed that the entrapment of transcription factors in aggregates plays an important role in pathogenesis. We now report that the transcriptional activity of CBP is already repressed in the early time points by soluble mutant huntingtin, whereas the histone acetylase activity of CBP/p300 is gradually diminished over time. Mutant huntingtin bound much stronger to CBP than normal huntingtin, possibly contributing to repression. Especially at the later time points, CBP protein level was gradually reduced via the proteasome pathway. In sharp contrast, p300 was unaffected by mutant huntingtin. This selective degradation of CBP was absent in spinocerebellar ataxia 3. Thus, mutant huntingtin specifically affects CBP and not p300 both at the early and later time points, via multiple mechanisms. In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyl transferases may affect chromatin structure and transcription and thus contribute to neurodegeneration.
 ...
PMID:Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. 1599 95

The lysine acetyltransferases type 3 (KAT3) family members CBP and p300 are important transcriptional co-activators, but their specific functions in adult post-mitotic neurons remain unclear. Here, we show that the combined elimination of both proteins in forebrain excitatory neurons of adult mice resulted in a rapidly progressing neurological phenotype associated with severe ataxia, dendritic retraction and reduced electrical activity. At the molecular level, we observed the downregulation of neuronal genes, as well as decreased H3K27 acetylation and pro-neural transcription factor binding at the promoters and enhancers of canonical neuronal genes. The combined deletion of CBP and p300 in hippocampal neurons resulted in the rapid loss of neuronal molecular identity without de- or transdifferentiation. Restoring CBP expression or lysine acetylation rescued neuronal-specific transcription in cultured neurons. Together, these experiments show that KAT3 proteins maintain the excitatory neuron identity through the regulation of histone acetylation at cell type-specific promoter and enhancer regions.
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PMID:KAT3-dependent acetylation of cell type-specific genes maintains neuronal identity in the adult mouse brain. 3244 94