Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

Abstract

A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated ageing and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases.

Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis

“…PARP1 acts as the SSB sensor that recruits other SSBR proteins, including XRCC1/LigIII, in a PARylation-dependent manner 26 , 28 , 29 . The basic BER/SSBR pathway involves four key reactions: (1) excision of the base lesion by a DNA glycosylase, (2) end-processing at the SSBs to generate 3′OH and 5′-phosphate ends, compatible with gap-filling synthesis and ligation, (3) gap-filling by a DNA polymerase, and (4) final nick sealing by a DNA ligase 33 . Nick sealing is the critical rate-limiting step in both BER and SSBR.…”

Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts

“…As Wang et al . (76) commented, “Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration.”…”

“…Oxidative damage to DNA by ROS is a significant cause of lesions that might promote AD progression; this would be consistent with the brain's particularly high consumption of oxygen, probably onefifth of the total oxygen consumed by the human body. As Wang et al (76) commented, "Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration. "…”

Is Alzheimer's disease linked to Herpes simplex virus type 1 infection? A mini‐review of the molecular correlation and the possible disease connections

“…HSV1 can cause oxidative stress through reactive oxygen species and reactive nitrogen species. [18][19][20] These aberrations caused by the stress are seen in fibroblasts and lymphoblastoid cells. The brain consumes one-fifth of the body's oxygen content; therefore, if the stress caused by HSV1 affected the brain, it would lead to the formation of plaques and lesions, which in turn would facilitate neurodegeneration.…”

“…17 Oxidative stress also leads to the damage of both single-stranded DNA and double-stranded DNA, which would affect the DNA repair process that could also be considered as one of the reasons for AD. [18][19][20] These aberrations caused by the stress are seen in fibroblasts and lymphoblastoid cells. 21,22 Damage to the lymphoblastoid cells facilitates AD.…”