Tuning acetylation levels with HAT activators: therapeutic strategy in neurodegenerative diseases.
Neurodegenerative diseases, such as polyglutamine-related diseases, amyotrophic lateral sclerosis, and Alzheimer's disease are accompanied by transcriptional dysfunctions, leading to neuronal death. It is becoming more evident that the chromatin acetylation status is impaired during the lifetime of neurons, by a common mechanism related to the loss of function of histone acetyltransferase (HAT) activity. Notably, the HAT termed cAMP response element binding protein (CREB)-binding protein (CBP) was shown to display neuroprotective functions. Several other HATs have now been shown to participate in basic but vital neuronal functions. In addition, there is increasing evidence of several HATs (including CBP), as essential regulators of neuronal plasticity and memory formation processes. In order to counteract neuronal loss and/or memory deficits in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules antagonizing histone deacetylase (HDAC) activity (i.e. HDAC inhibitors). Although this strategy lacks specificity, some of these molecules display promising therapeutic properties. With the rapidly evolving literature on HATs and their respective functions in neuronal survival and memory formation, it seems essential to envisage direct stimulation of the acetyltransferase function as a new therapeutic tool in neurodegenerative diseases. In this review, we will highlight the present understanding and the future prospects of such therapeutic approach.
Selvi
B Ruthrotha
BR
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560 064, India.
Cassel
Jean-Christophe
JC
Kundu
Tapas K
TK
Boutillier
Anne-Laurence
AL
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism*; D020536:Enzyme Activators / Q000737:chemistry / Q000627:therapeutic use*; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D008568:Memory / Q000187:drug effects*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000201:enzymology / Q000473:pathology
D002843:Chromatin; D020536:Enzyme Activators; D056572:Histone Deacetylase Inhibitors; D051548:Histone Acetyltransferases