TY - JOUR
T1 - Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration
T2 - Is damage response signaling a potential therapeutic target?
AU - Wang, Haibo
AU - Dharmalingam, Prakash
AU - Vasquez, Velmarini
AU - Mitra, Joy
AU - Boldogh, Istvan
AU - Rao, K. S.
AU - Kent, Thomas A.
AU - Mitra, Sankar
AU - Hegde, Muralidhar L.
PY - 2016/9/20
Y1 - 2016/9/20
N2 - 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 aging 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.
AB - 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 aging 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.
KW - DNA damage
KW - DNA damage response
KW - DNA repair defects
KW - Neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=85001060904&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85001060904&partnerID=8YFLogxK
U2 - 10.1016/j.mad.2016.09.005
DO - 10.1016/j.mad.2016.09.005
M3 - Article
C2 - 27663141
SN - 0047-6374
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
ER -