| Neurodegeneration leads to significant physiological dysfunction in both neuron-specific processes and the organ systems controlled by neuronal input. The adult nervous system is unable to execute any significant regeneration process to replace the dead neurons, thus the loss of function after neurodegeneration is permanent. Therefore, early prevention of neuronal loss in neurodegenerative diseases is critical. In many neurodegenerative processes, the initiating factor for the activation of cell death may be secondary cell stress, such as DNA damage. Indeed, post-mitotic neurons are extremely sensitive to DNA damage, demonstrated by the frequency of neuropathic side effects that complicates the management of patients undergoing cancer chemotherapy and anti-viral treatment. Understanding the molecular mechanisms underlying neuronal cell death induced by DNA damage may suggest new therapeutic targets for the treatment of neurodegeneration and enable us to develop new-generation chemotherapeutic and anti-viral drugs that are not neurotoxic.; Using in vitro models of post-mitotic primary neurons, we identified neuronal proteins and signaling pathways that are important for DNA-damage-induced death. Genotoxic stress induced BH3-only proteins Bim and PUMA, which was followed by Bax-dependent mitochondrial cytochrome-c release, rapid caspase activation and neuronal apoptosis. When this rapid death was blocked by genetic deletion of bax, or caspase inhibition, neurons activated a slower, Bax-independent death pathway.; DNA-damage-induced neuronal death was associated with the activation of AP-1 transcription factor c-Jun. In contrast to many other neuronal death paradigms, c-Jun activation and DNA-damage-induced neuronal apoptosis did not require the stimulation of the Jun-N-terminal kinase (JNK). c-Jun phosphorylation by this novel, JNK-independent pathway accelerated neuronal apoptosis.; Before the activation of the proapoptotic transcription factor c-Jun and the Bax-dependent mitochondrial cell death pathway, neurons displayed significant increase in protein kinase D (PKD) activation both in vitro and in vivo after DNA damage. Unique characteristics of PKD, including immediate stimulation after exposure DNA damage, simultaneous activation with another early marker of DNA damage, ataxia-telangiectasia mutated (ATM), and exclusive response to genotoxic stress, but not other apoptotic insults, strongly indicated that PKD was an early marker for DNA damage and might be involved in cellular response to DNA lesions. |
