Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

Abstract

The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype

“…11,16 After exposure to UVB, there was a rapid drop of 6-4PPs resulting in 70 ± 7% and 72 ± 8% removal of 6-4PPs 2.5 h post-irradiation in control and patient fibroblast, respectively (Figure 4b). The gradual repair of 6-4PPs in the next hours led to 93 ± 5% and 94 ± 6% removal by 20 h in control and patient fibroblasts, respectively (Figure 4b).…”

“…15 It was suggested that correct DNA repair is required for maintenance of the functional integrity of the nervous system by preventing the premature death of neurons. 11 Further studies are needed to explain the pathophysiological link between these phenomenons.…”

Dysmyelination not demyelination causes neurological symptoms in preweaned mice in a murine model of Cockayne syndrome

“…In humans and mice the cerebellum shows distinctive atrophy with loss of Purkinje cells that are associated with regulating balance and walking (4,5). The brains of CS patients and mice have shown evidence for accumulation of unrepaired damage (6,7).…”

“…The brains of CS patients and mice have shown evidence for accumulation of unrepaired damage (6,7). The brain shows reduced numbers of oligodendrocytes and less myelination, but it remains unclear whether the disease is primarily one of neurodegeneration with neuronal and myelin loss (demyelination) or a failure of oligodendrocyte differentiation and myelin synthesis (dysmyelination) (4).…”

“…Suggestions have been made that CS caused by faulty responses to endogenously generated oxidative damage through additional deficiencies in base excision repair (18), mitochondrial activity (22), and coordination of a transcriptional response (4,23). However, although CSA and CSB patients have indistinguishable clinical disease, only CSB and not CSA or UV s cells are sensitive to oxidative damage (14,17,24).…”