Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders
Section snippets
Apoptosis and neurodegenerative diseases
Apoptosis is a physiological programmed cell death that allows the control of cellular homeostasis during development. In the adult, apoptosis guides the fate of individual cells or organs. Nevertheless, it can also be activated under pathological conditions, notably in the central nervous system. Indeed, post-mortem analyses of human brains and in vivo animal models gave evidence of programmed cell death in different neurodegenerative diseases, reviewed in Ref. [1]. Apoptotic hallmarks were
Transcriptional modifications during neuronal apoptosis
As an active cell death, apoptosis occurs with transcriptional modifications leading to activation of pro-apototic genes and repression of neuroprotective genes [16], [17], [18]. Indeed, transcription/translation inhibitors prevent or delay apoptosis in response to a wide range of insults [11], [19]. However, the fine mechanisms of transcriptional regulation implicated in apoptosis are still obscure, particularly because the deep changes occurring on chromatin during this process, i.e. global
CBP loss of function in neurological disorders
Interestingly, CBP loss of function has been linked to several neuropathologies. The earliest described was the Rubinstein–Taybi syndrome (RTS), an autosomal dominant syndrome characterized by mental retardation and skeletal malformations [37], [38]. Alterations in cbp gene were reported to be the cause of RTS [39]. Recent studies suggest that mutations affecting cbp gene in RTS patients would mainly target the HAT domain, leading to abolition of CBP HAT activity as well as its ability to
Mechanisms leading to CBP loss of function
Several mechanisms account for the observed CBP loss of function. cbp haploinsufficiency responsible for RTS leads to an insufficient amount of produced functional CBP [39]. cbp heterozygous-deficient mice present abnormal skeletal patterning [49] and deficiencies in long-term memory [50], whereas cbp diploinsufficiency induces embryonic death [49], [51]. These observations suggest a role of CBP during development and during CNS formation in particular. Besides genetic alterations, CBP loss of
HDAC inhibition as a therapeutic strategy
As protein acetylation levels result from a balance of HAT and HDAC activities, several laboratories have investigated the possibility of compensating for decreased acetylation levels observed during neurodegeneration by pharmacological inhibition of the HDAC function (Fig. 3). A variety of HDAC inhibitors have been tested, such as trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) or sodium butyrate (NaBu). TSA and SAHA were shown to reduce neuronal loss in an in vitro model of SBMA
CBP over-expression
One means of counteracting CBP loss of function, preserving both HAT and co-activator functions, would be to over-express the protein (Fig. 3). This approach has already been investigated in a polyQ disease model such as transgenic Drosophila over-expressing htt, in which CBP up-regulation could not only restore the histone acetylation levels and the transcriptional regulation, but could also reduce both polyQ-induced aggregation and neurodegeneration [56]. In an SBMA model, CBP over-expression
Acknowledgements
We wish to thank Dr. L. Dupuis for critical reading of the manuscript. C.R. is a recipient of a fellowship from the French Research Ministry. The laboratory is supported by grants from “Association pour la Recherche sur la SLA” (ARS), “Association pour la Recherche et le développement de moyens de lutte contre les Maladies Neurodégénératives” (AREMANE), “Association pour la Recherche contre le Cancer” (ARC Nos. 4306 and 7653), “France Alzheimer” and Aventis Pharma.
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