Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA damage in neurons is implicated in the pathogenesis of several neurodegenerative disorders and may also contribute to the often severe neurological complications in cancer patients treated with chemotherapeutic agents. DNA damage can trigger apoptosis, a form of controlled cell death that involves activation of cysteine proteases called caspases. The excitatory neurotransmitter glutamate plays central roles in the activation of neurons and in processes such as learning and memory, but overactivation of ionotropic glutamate receptors can induce either apoptosis or necrosis. Glutamate receptors of the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate) type mediate such physiological and pathological processes in most neurons. We now report that DNA damage can alter glutamate receptor channel activity by a mechanism involving activation of caspases. Whole-cell patch clamp analyses revealed a marked decrease in AMPA-induced currents after exposure of neurons to camptothecin, a topoisomerase inhibitor that induces DNA damage; N-methyl-d-aspartate (NMDA)-induced currents were unaffected by camptothecin. The decrease in AMPA-induced current was accompanied by a decreased calcium response to AMPA. Pharmacological inhibition of caspases abolished the effects of camptothecin on AMPA-induced current and calcium responses, and promoted excitotoxic necrosis. Combined treatment with glutamate receptor antagonists and a caspase inhibitor prevented camptothecin-induced neuronal death. Caspase-mediated suppression of AMPA currents may allow neurons with damaged DNA to withdraw their participation in excitatory circuits and undergo apoptosis, thereby avoiding widespread necrosis. These findings have important implications for treatment of patients with cancer and neurodegenerative disorders.
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PMID:Caspase-mediated suppression of glutamate (AMPA) receptor channel activity in hippocampal neurons in response to DNA damage promotes apoptosis and prevents necrosis: implications for neurological side effects of cancer therapy and neurodegenerative disorders. 1130 Jul 17

Angelman syndrome (AS) is characterized by severe intellectual disability, epilepsy and ataxic motor dysfunction. Paternally imprinted UBE3A, which is located in the imprinted domain of 15q11-q13, is the causative gene of AS. UBE3A is exclusively expressed from the maternally inherited allele only in neurons (neuron-specific imprinting), and is regulated by antisense RNA. UBE3A is an E3 ubiquitin protein ligase and Arc is one of its targets in the brain. Arc is known to regulate AMPA-type glutamate receptor at the post-synaptic membrane. Loss-of-function of UBE3A results in upregulation of Arc and downregulation of AMPA receptors, giving rise to disturbance in experience-dependent synaptic plasticity. Unraveling the pathophysiology of AS will shed light on the development of pharmaceutical agents for genetic intellectual disabilities. Recently, topoisomerase inhibitors were shown to unsilence imprinted Ube3a in a mouse model of AS. This success indicated the possibility of an epigenetic therapy for AS. Therefore, AS is also a good model for the development of epigenetic therapy for genetic intellectual disorders caused by epigenetic dysfunction.
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PMID:[From pathogenesis to treatment of genetic intellectual disabilities: a lesson from Angelman syndrome research]. 2506 46