Inhibition of ataxia telangiectasia-p53-E2F-1 pathway in neurons as a target for the prevention of neuronal apoptosis.
Over the last few decades, understanding of the mechanisms involved in the process of neuronal cell death has grown. Recent findings have established that DNA damage, and specifically ataxia telangiectasia mutated protein (ATM), is key to the cascade of regulation of neuronal apoptosis. Another characteristic common to all neurodegenerative diseases is oxidative stress. Likewise, a common feature in the brain of patients with neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and other neurological disorders is the expression of proteins involved in cell-cycle control. In the process of re-entry in the cell cycle, an additional component, transcription factor E2F-1, also involved in the regulation of apoptosis, is expressed. Finally, in this complex puzzle, mitochondrial activation with the release of proteins and the activation of cystein proteases, specifically caspase-3, is prominent in the last step of neuronal apoptosis. This review focuses on the role of ATM activation and its re-entry into the cell cycle in neurons as a potential target for the prevention of neuronal apoptosis. We suggest the mechanisms by which ATM and E2F-1 orchestrate the apoptotic process. Among them, p53 could be a common point on this apoptotic route. Finally, we put forward drugs that are now being studied experimentally, such as p53 inhibitors, ATM inhibitors and cyclin-dependent kinase (CDKs) inhibitors, for the treatment of neurodegenerative diseases.
Camins
Antoni
A
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028, Barcelona, Spain. camins@ub.edu
Verdaguer
Ester
E
Folch
Jaume
J
Beas-Zarate
Carlos
C
Canudas
Anna Maria
AM
Pallàs
Mercè
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D050687:E2F1 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D018696:Neuroprotective Agents; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases