Lysine acetyltransferases CBP and p300 as therapeutic targets in cognitive and neurodegenerative disorders

Abstract

Neuropsychiatric pathologies, including neurodegenerative diseases and neurodevelopmental syndromes, are frequently associated with dysregulation of various essential cellular mechanisms, such as transcription, mitochondrial respiration and protein degradation. In these complex scenarios, it is difficult to pinpoint the specific molecular dysfunction that initiated the pathology or that led to the fatal cascade of events that ends with the death of the neuron. Among the possible original factors, epigenetic dysregulation has attracted special attention. This review focuses on two highly related epigenetic factors that are directly involved in a number of neurological disorders, the lysine acetyltransferases CREB-binding protein (CBP) and E1A-associated protein p300 (p300). We first comment on the role of chromatin acetylation and the enzymes that control it, particularly CBP and p300, in neuronal plasticity and cognition. Next, we describe the involvement of these proteins in intellectual disability and in different neurodegenerative diseases. Finally, we discuss the potential of ameliorative strategies targeting CBP/p300 for the treatment of these disorders.

Fig. (1)

KATs and HDAC classes. Schematic depicting the balance of KAT and HDAC activities and the impact of this balance on chromatin conformation. The presence of acetyl groups (black balls) in the nucleosome histone tails relaxes the chromatin and facilitates the access of transcription factors. The boxes show the general classification of KAT and HDAC proteins and list representative examples for each group. For the KATs, we used the new nomenclature, but the former name or names are also indicated [30]. See the review articles [31, 156] for additional details.

Fig. (2)

Structure of KAT3 proteins. CBP and p300 share a number of structural domains including three cysteine/histidine rich regions (CH1-CH3) for protein-protein interaction, the KIX domain that mediates the interaction with CREB and other transcription factors, and the KAT domain. The domains of highest homology and the percentage of amino acid identity between the two proteins are indicated. Regions of high homology between the human CBP and p300 proteins expressed as % identity. NRID, nuclear hormone receptor interacting domain; CH1-3, cysteine/histidine-rich regions 1-3; TAZ1-2, transcriptional adaptor Zn-finger domain 1-2; KIX, kinase inducible domain; Br, bromodomain; PHD, plant homeodomain; ZZ, ZZ-type Zn-finger domain; SID, SRC- 1 interacting domain; MDM2, p53 E3-ubiquitin protein ligase homolog; ATF, activation transcription factors; TBP, TATA-binding protein. Figure modified from [52].

Fig. (3)

Summary of neuropathologies related to KAT3 proteins and therapeutic approaches targeted to these proteins. The balance between KATs and HDACs define the optimal level of chromatin acetylation required for developmental and cognitive functions. The alteration of this balance, favoring either histone hyperacetylation (right box) or hypoacetylation (left box), may result in cognitive impairment and/or deleterious effects. This is the case of well-known pathological conditions like the Rubinstein-Taybi syndrome (RSTS), Fetal Alcohol Spectrum Disorder (FASD), Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and other neurological disorders. Therapeutic approaches aimed at restoring the balance, including HDAC inhibitors (HDACis), KAT enhancers (KATes) and inhibitors (KATis) and genetic overexpression of KAT3 genes, are indicated under the corresponding boxes.