Chromatin acetylation status in the manifestation of neurodegenerative diseases: HDAC inhibitors as therapeutic tools.
During the development and maintenance of the central nervous system, neurons receive specific instructions to differentiate, survive or die, the correct choice being crucial for the maturation of a functional brain and to face pathological conditions. At the transcriptional level, chromatin remodeling enzymes participates in such processes. In this paper, we will see that disruption of the Histone acetyl transferase (HAT)/Deacetylase (HDAC) balance is often observed in different contexts of neurological disorders and more particularly during neuronal apoptosis. During the last 5 years, it has been evidenced that the chromatin acetylation status was greatly impaired in different neurodegenerative diseases, a common mechanism being the loss of function of a specific HAT: the CREB-binding protein (CBP). We will review the last attempts of the use of small molecules antagonizing HDAC activity (HDAC inhibitors) to restore proper levels of acetylation and enhance neuronal survival, both in in vitro and in vivo models of neurodegenerative diseases such as polyglutamine-related diseases and amyotrophic lateral sclerosis. Although this strategy lacks specificity towards CBP, certain of these molecules display promising therapeutic properties
Anne-Laurence
Boutillier
B
Laboratoire de Signalisation Moléculaire et Neurodégénérescence--INSERM U692 11, rue Humann, 67085 Strasbourg, France. laurette@neurochem.u-strasbg.fr
Caroline
Rouaux
R
Irina
Panteleeva
P
Jean-Philippe
Loeffler
L
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050882:CREB-Binding Protein / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*
D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007527:Isoenzymes; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases