The transcription factor CREB -- for 'cyclic AMP response element-binding protein' -- functions in glucose homeostasis, growth-factor-dependent cell survival, and has been implicated in learning and memory. CREB is phosphorylated in response to various signals, but how is specificity achieved in these signalling pathways?

Transcriptional regulation by the phosphorylation-dependent factor CREB

Expanded polyglutamine repeats have been proposed to cause neuronal degeneration in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short polyglutamine tracts such as the transcriptional coactivator CREB binding protein, CBP. We found that CBP was depleted from its normal nuclear location and was present in polyglutamine aggregates in HD cell culture models, HD transgenic mice, and human HD postmortem brain. Expanded polyglutamine repeats specifically interfere with CBP-activated gene transcription, and overexpression of CBP rescued polyglutamine-induced neuronal toxicity. Thus, polyglutamine-mediated interference with CBP-regulated gene transcription may constitute a genetic gain of function, underlying the pathogenesis of polyglutamine disorders.

https://science.sciencemag.org/content/sci/291/5512/2423.full.pdf

Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity

Transcriptional repression of PGC-1α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration

Summary Autosomal dominant cerebellar ataxias are hereditary neurodegenerative disorders that are known as spinocerebellar ataxias (SCA) in genetic nomenclature. In the pregenomic era, ataxias were some of the most poorly understood neurological disorders; the unravelling of their molecular basis enabled precise diagnosis in vivo and explained many clinical phenomena such as anticipation and variable phenotypes even within one family. However, the discovery of many ataxia genes and loci in the past decade threatens to cause more confusion than optimism among clinicians. Therefore, the provision of guidance for genetic testing according to clinical findings and frequencies of SCA subtypes in different ethnic groups is a major challenge. The identification of ataxia genes raises hope that essential pathogenetic mechanisms causing SCA will become more and more apparent. Elucidation of the pathogenesis of SCA hopefully will enable the development of rational therapies for this group of disorders, which currently can only be treated symptomatically.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474442204007379.pdf

Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis.

The cyclic AMP-responsive element-binding protein (CREB) is phosphorylated in response to a wide variety of signals, yet target gene transcription is only increased in a subset of cases. Recent studies indicate that CREB functions in concert with a family of latent cytoplasmic co-activators called cAMP-regulated transcriptional co-activators (CRTCs), which are activated through dephosphorylation. A dual requirement for CREB phosphorylation and CRTC dephosphorylation is likely to explain how these activator-co-activator cognates discriminate between different stimuli. Following their activation, CREB and CRTCs mediate the effects of fasting and feeding signals on the expression of metabolic programmes in insulin-sensitive tissues.

CREB and the CRTC co-activators: sensors for hormonal and metabolic signals.

At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded polyQ stretches preferentially bind to TAFII130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAFII130. Our results indicate that interference of transcription by the binding of TAFII130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.

Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription.

Expanded polyglutamine stretches have been shown to form aggregates and to be toxic to cells. In this study, we hypothesized that amino acid sequences flanking the polyglutamine stretches influence the aggregate formation potential of these stretches. Green fluorescent protein (GFP) fusion proteins containing glutamine repeats of various lengths and a fixed number of flanking amino acids of ataxin-2, huntingtin, dentatorubral-pallidoluysian atrophy protein (DRPLAP) or ataxin-3 were transiently expressed in COS-7 cells. The aggregate formation potential of ataxin-2 and DRPLAP increased in a CAG-repeat-length-dependent manner, with a threshold between 34 and 36. Truncated ataxin-2-Q56-GFP and truncated huntingtin-Q56-GFP showed a significantly higher aggregate formation potential than truncated DRPLAP-Q56-GFP or truncated ataxin-3-Q56-GFP. These results are in agreement with the clinical observation that ages of disease onset in patients with spinocerebellar ataxia type 2 or Huntington's disease are lower than those in patients with DRPLA or Machado-Joseph disease having expanded CAG repeats of the same length. Furthermore, mutagenesis of the flanking sequence of ataxin-2 markedly reduced its aggregate formation potential. These results indicate that the amino acid sequences flanking the polyglutamine stretches significantly influence their aggregate formation potential.

Amino acid sequences flanking polyglutamine stretches influence their potential for aggregate formation.

Transcriptional dysregulation, particularly cAMP-responsive-ele ment-mediated transcriptional repression, has been implicated it expanded polyglutamine diseases. However, it has not been clari fied whether this transcriptional repression is a cause or result o neurodegeneration. Furthermore, the association between aggre gates of expanded polyglutamine stretches and transcriptional re pression is not clear. We established isogenic cell lines with polyglutamine stretches, which also expressed d2EGFP under th< control of cAMP-responsive elements. In this system, the polyglu tamine stretch repressed cAMP-responsive-element-mediated n transcription without the formation of macroscopic expanded i- polyglutamine aggregates. Furthermore, aggregate formation if did not have an adverse effect on the repression of transcriptional activity. The results demonstrated that the repression of cAMPresponsive-element-mediated transcription is an early event h caused by a soluble form of polyglutamine stretch.

Kenkichi Nozaki

Papers

Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription.

Amino acid sequences flanking polyglutamine stretches influence their potential for aggregate formation.

Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation.