The integrity of our DNA is under constant attack from numerous endogenous and exogenous agents. The consequences of defective DNA and DNA damage responses (DDRs) have been extensively studied in fast proliferating cells, especially in connection to cancer, yet their precise roles in the nervous system are relatively poorly understood.
Two fundamental questions are still open:
What is the integrity of the genome in the adult and aging brain?
What is the role of DNA damage in aging and neurodegenerative disorders such as Alzheimer’s disease (AD) or Parkinson’s disease (PD)?
How damaged is the genome in the adult brain?
The neurons of our nervous system are post-mitotic, meaning that once matured, they cannot rely on cell division to replace a lost or disabled neighbour. This fact has two important consequences:
- In a long-lived species such as homo sapiens, a ‘lucky’ CNS neuron may survive for 80 years or more, potentially accumulating a lot of DNA damage.
- Neurons are devoid of homologous recombination – the most effective way to repair DNA double stranded breaks -which takes place mainly during cell division.
The genome integrity in the adult brain is still the object of intense scrutiny but what is generally accepted is that the adult brain tolerates an unexpected degree of DNA damage and that the DDR mechanisms might be significantly different from other somatic cells.
What is the role of DNA damage in aging and neurodegenerative disorders?
As we have already observed, neurons are particularly prone to accumulating DNA defects with age, the key question here is whether these defects contribute to developing and/or sustaining neurodegeneration.
Several pieces of evidence seem to point in this direction. For example, age is the most common risk factor for most adult-onset neurodegenerative diseases with even the most aggressive familial forms of dementia rarely striking before the age of 40 years.
What is still unclear is how DNA damage contributes to the development of pathologies such as AD and PD that are regional by nature, e.g. involve only specific areas of the brain.
On this regard, several models and theories have been suggested but none of them has been fully validated yet with sufficient data (Fig.1).
Fig.1 Models to explain the relationship between age, DNA damage and neurodegeneration. (from: ‘Chow, H-m; Herrup, K. Genomic integrity and the ageing brain’, NATURE REVIEWS NEUROSCIENCE, 2015; 16, p 672)
Clearly, answering to some of these questions could open new exciting avenues in the field of neurodegeneration, an area that unfortunately is increasingly neglected by big pharma after the clinical failures of the last decade.
It is definitely time for DDR research to focus on the brain!
Blog written by Alessandro Mazzacani
‘Genomic integrity and the ageing brain’, Hei-man Chow and Karl Herrup, NATURE REVIEWS NEUROSCIENCE, 16, NOVEMBER 2015, p 672
‘DNA Damage and Its Links to Neurodegeneration’ Ram Madabhushi, Ling Pan,and Li-Huei Tsai, Neuron, 83, July 2014, p 266