【摘 要】
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Accumulation of DNA damage and genomic instability are believed to have crucial effects in neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, premature aging diseases as well as amyotrophic lateral scleros
【机 构】
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Translational Neurodegeneration Section“Albrecht-Kossel”,Department of Neurology,University Medical
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Accumulation of DNA damage and genomic instability are believed to have crucial effects in neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, premature aging diseases as well as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Until recently these studies were largely correlative in nature, though raising the possibility that defects in the DNA damage response (DDR) underlie neurodegenerative diseases. However, more light needs to be shed on (a) the identification of specific lesions, if existing, and their propensity to accumulate in the affected neurons of a given neurodegenerative disease; (b) the underlying mechanisms that impede the repair of these lesions; and based on that (c) the development of animal model systems harboring these identified lesions that are central to progression of neurodegenerative disease in order to see, if interventional strategies that promote DNA repair can alleviate these effects and lead to novel mechanism-driven approaches in drug development to combat neurodegenerative diseases (Madabhushi et al., 2014). It is established that the nervous system requires the largest part of the oxygen consumption producing higher levels of reactive oxygen species (ROS) as a side product, which are known for their oxidative stress on cells in general. Focussing on neurons, ROS are one of the major sources for genotoxic stress producing more than 100 different oxidative base modifications with strong mutagenic potential, which can easily be converted to single strand breaks (SSB) (Madabhushi et al., 2014). Therefore, neurons are particularly dependent on efficient base excision repair and single strand repair processes (Figure 1), which is reflected by the volume of neurological disorders caused by defects in these repair pathways (Madabhushi et al., 2014). This highlights the pivotal role of DNA damage and the biological response mechanisms to it as a presumably early event in the process of neurodegeneration.
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