Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders Caroline Rouaux, Jean-Philippe Loeffler, Anne-Laurence Boutillier * Laboratoire de Signalisation Mole ´culaire et Neurode ´ge ´ne ´rescence - EA#3433 11, rue Humann, 67085 Strasbourg Cedex, France Received 30 March 2004; accepted 24 May 2004 Abstract Histone acetylation/deacetylation is a master regulation of gene expression. Among the enzymes involved in this process, the CREB- binding protein (CBP) displays important functions during central nervous system development. Increasing evidence shows that CBP function is altered during neurodegenerative processes. CBP loss of function has now been reported in several diseases characterized by neurological disorders such as the Rubinstein–Taybi syndrome or polyglutamine-related pathologies (Huntington’s disease). Our recent work suggests that CBP loss of function could also be involved in Alzheimer’s disease and amyotrophic lateral sclerosis. In a simplified apoptotic model of primary neurons, we described CBP as a substrate of apoptotic caspases, an alternative to its classical proteasomal degradation. In these neuronal death contexts, histone acetylation levels were decreased as well. Altogether, these data point to a central role of CBP loss of function during neurodegeneration. In order to restore proper acetylation levels, a proposed therapeutic strategy relies on HDAC inhibition. Nevertheless, this approach lacks of specificity. Therefore new drugs targeted at counteracting CBP loss of function could stand as a valid therapeutic approach in neurodegenerative disorders. The challenge will be to respect the fine-tuning between cellular HAT/HDAC activities. # 2004 Elsevier Inc. All rights reserved. Keywords: CBP; Histone acetylation; Neurodegenerative diseases; Apoptosis; Caspase-6; HDAC inhibitors 1. 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 found in Alzheimer’s disease [2,3], Parkinson’s disease [4], Huntington’s disease [5] and amyotrophic lateral sclerosis [6,7]. Neuronal apoptosis can be modeled in vitro with primary neuronal cultures. For example, this active form of cell death is induced by K þ -starvation of cerebellar granule neurons (CGN) from 7-day-old mice [8–10]. This model presents classical morphological and biochemical hall- marks of apoptosis such as cell shrinkage, chromatin condensation and nuclear fragmentation [9,11], accompa- nied with internucleosomal DNA fragmentation and cas- pases activation that are responsible for the degradation of neuroprotective proteins [12,13]. Cytochrome c release from mitochondria [14] and up-regulation of pro-apototic factors [15,16] were also described in this model. 2. Transcriptional modifications during neuronal apoptosis As an active cell death, apoptosis occurs with transcrip- tional modifications leading to activation of pro-apototic Biochemical Pharmacology 68 (2004) 1157–1164 0006-2952/$ – see front matter # 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bcp.2004.05.035 Abbreviations: CBP, CREB-binding protein; CREB, cyclic AMP- responsive element-binding protein; HAT, histone acetyltransferase; HDAC, histone deacetylase; CGN, cerebellar granule neurons; RTS, Rubinstein– Taybi syndrome; AD, Alzheimer’s disease; APP, amyloid precursor protein; ALS, amyotrophic lateral sclerosis; HD, Huntington’s disease; htt, Huntingtin; SBMA, spinal and bulbar muscular atrophy; TSA, trichostatin A; SAHA, suberoylanilide hydroxamic acid; NaBu, sodium butyrate * Corresponding author. Tel.: þ33 390 24 30 82; fax: þ33 390 24 30 65. E-mail address: laurette@neurochem.u-strasbg.fr (A.-L. Boutillier).