Loss of the Xeroderma Pigmentosum Group A Gene (XPA) Enhances Apoptosis of Cultured Cerebellar Neurons Induced by UV but Not by Low‐K⁺ Medium

Abstract

To study the involvement of the xeroderma pigmentosum group A gene (XPA) in neuronal apoptosis, we cultured cerebellar neurons from mice lacking XPA gene (XPA~)and induced apoptosis by exposure to UV irradiation or medium containing a low concentration of potassium (low-Kmedium). When cerebellar neurons from postnatal days 15-16 wild-type mice were treated with UV irradiation, apoptotic neuronal death was observed after 24-48 h. About 60% of neurons survived 48 h after UV irradiation at a dose of 5 J/m 2. On the other hand, neurons from XPA~mice showed a significantly increased vulnerability to UV irradiation, and >90% of neurons died 48 h after UV irradiation at a dose of 5 J/ m2. In contrast, low-K~medium induced apoptosis of neurons from mice of each genotype with the same kinetics. These results suggest that the XPA gene is involved in neuronal DNA repair and that it thereby influences apoptosis induced by DNA damage in cultured cerebellar neurons.

Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology

“…However, in Xpa −/− mice the phenotype is very different from the severe progressive neurodegenerative changes of many XP-A patients, which develop juvenile or adult progressive neuronal degeneration throughout the central and peripheral nervous system depending on the severity of NER dysfunction [17], [19], [33], [34], [36]. Neurons from Xpa −/− mice display considerably increased sensitivity to UV radiation [77] and the cross-linking agent cisplatin [78], consistent with loss of NER function and excluding redundancy of NER activity by other proteins at least for the lesions induced by these agents. The discrepancies between human and rodents may follow from differences in the rate of production and type of DNA lesions caused by endogenous metabolites, and from the shorter lifespan of mice.…”

Role of DNA‐dependent protein kinase in neuronal survival

“…Prior work showed that post‐mitotic neurons are highly sensitive to deficits in DNA repair enzymes and this deficiency can lead to neurodegeneration (Robbins et al . 1983; Enokido et al . 1997; Gao et al .…”

Cockayne syndrome pathogenesis: Lessons from mouse models

“…In patients deficiency of NER is sufficient to cause juvenile or adult onset progressive neuronal degeneration throughout the central and peripheral nervous system (Anttinen et al, 2008;Kraemer and DiGiovanna, 2003;Kraemer et al, 2007;Mimaki et al, 1996). In contrast, totally NER-defective Xpa À/À mutant mice do not develop motor or behavioral abnormalities (Melis et al, 2008;Nakane et al, 2008), although neurons from Xpa À/À mice display increased sensitivity to UV (Enokido et al, 1997) and the cross-linking agent cisplatin (Dzagnidze et al, 2007). We found that Xpa À/À animals, like Xpc À/À mice, develop a marginal nervous system phenotype consisting of highly sporadic p53-immunoreactive neurons and astrocytes .…”