The complex mechanisms by which neurons die following DNA damage in neurodegenerative diseases

Human cells are exposed to numerous exogenous and endogenous insults every day. Unlike other molecules, DNA cannot be replaced by resynthesis, hence damage to DNA can have major consequences for the cell. The DNA damage response contains overlapping signalling networks that repair DNA and hence maintain genomic integrity, and aberrant DNA damage responses are increasingly described in neurodegenerative diseases. Furthermore, DNA repair declines during aging, which is the biggest risk factor for these conditions. If unrepaired, the accumulation of DNA damage results in death to eliminate cells with defective genomes. This is particularly important for postmitotic neurons because they have a limited capacity to proliferate, thus they must be maintained for life. Neuronal death is thus an important process in neurodegenerative disorders. In addition, the inability of neurons to divide renders them susceptible to senescence or re-entry to the cell cycle. The field of cell death has expanded significantly in recent years, and many new mechanisms have been described in various cell types, including neurons. Several of these mechanisms are linked to DNA damage. In this review, we provide an overview of the cell death pathways induced by DNA damage that are relevant to neurons and discuss the possible involvement of these mechanisms in neurodegenerative conditions.