Control and Dysregulation of Gene Transcription in Neurodegeneration

What underlies transcriptional dysregulation In the case of PD, mutations in transcriptional factors themselves are an emerging theme. Two recent genetic association studies in a screening sample of large cohorts of individuals with idiopathic PD have revealed evidence for a novel association of PITX3 promoter 

The consequence of a reduction in HAT-mediated gene transcription is exemplified by Rubenstein-Taybi syndrome (RTS). RTS is caused by mutations in the CBP gene, which leads to an insufficient amount of produced functional CBP. The disease is characterized by developmental abnormalities and mental retardation. A number of mouse models with CBP mutations have been developed. These mice exhibit histone hypo-acetylation due to impaired CBP function, transcriptional repression, and memory impairment, while homozygous knockouts are embryonic lethal (reviewed in [178]). Thus, sequestration of CBP into insoluble protein aggregates may well be expected to phenocopy some aspects of RTS pathology. 

TBP is a key transcriptional factor required for transcriptional initiation by the three major RNA polymerases (RNAP I, II, and III) and is involved in gene expression of most eukaryotic genes. Expanding the polyQ stretch of TBP from 31Q into the pathogenic range of 71 Q reduced in vitro binding of TBP to the TATA box DNA [181]. In a SCA-17 mouse model, N-terminal TBP fragments are present, which harbor the expanded polyQ tract but lack an intact C-terminal 

DNA-binding domain. This polyQ-expanded TBP, incapable of binding DNA, formed nuclear inclusions and caused a severe neurological phenotype in transgenic mice. Together, these results indicate that polyQ-expanded TBP is inhibitory to TATA-dependent transcription as it is unable to bind DNA productively [181,182]. PolyQ-expanded Htt exon 1 protein has also been shown to bind and sequester TBP [183]. In the case of mutant ataxin-7, HAT activity of the STAGA complex is compromised, and this has been directly linked to the retinal degeneration common in this disease [184, 185]. Transcriptional abnormalities have also been detected in ALS patients and mouse models thereof [186-188]. 

In atro-118Q transgenic mice, neuronal expression of the mutant human atrophin-1 protein containing an expanded stretch of 118 polyQ results in several neurodegenerative phenotypes that are commonly seen in DRPLA patients. Symptoms include ataxia, tremors, and other motor defects. Biochemical analysis of these mice also revealed histone H3 hypo-acetylation in brain tissue [197]. Furthermore, histone hypo-acetylation has also been demonstrated in transgenic ALS mice [198]. 

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