DNA strand breaks, neurodegeneration and aging in the brain

Abstract

Defective responses to DNA single- or double-strand breaks can result in neurological disease, underscoring the critical importance of DNA repair for neural homeostasis. Human DNA repair-deficient syndromes are generally congenital, in which brain pathology reflects the consequences of developmentally incurred DNA damage. Although, it is unclear to what degree DNA strand-break repair defects in mature neural cells contributes to disease pathology. However, DNA single-strand breaks are a relatively common lesion which if not repaired can impact cells via interference with transcription. Thus, this lesion, and probably to a lesser extent DNA double-strand breaks, may be particularly relevant to aging in the neural cell population. In this review we will examine the consequences of defective DNA strand-break repair towards homeostasis in the brain. Further, we also consider the utility of mouse models as reagents to understand the connection between DNA strand breaks and aging in the brain.

Figure 1. The adult mammalian CNS

The mature nervous system contains a myriad of different cell types and tissues. DNA repair processes impact substantially during neural development leading to defective neurogenesis and development. However, less is known regarding the requirement for DNA repair processes in mature neural cell. Inset panels are hematoxylin and eosin stained retinal and cerebellar sections that show cell organization in these tissues. The retina is laminar in nature and cell-types are stratified into three distinct nuclear layers: outer, inner and ganglion. The outer nuclear layer contains the photoreceptor (rods and cones) neurons. The inner nuclear layer contains various signal processing cell types: bipolar, horizontal, amacrine, interplexiform and the Müller glia. The ganglion cells carry the visual signal via its axons through the optic nerve and project onto the brain. The cerebellum is stratified into three primary layers: inner granule cell layer, the Purkinje cell layer and the molecular layer. Excitory sensory signals originating from the cerebellum are ultimately transmitted through granule-Purkinje synapses and out of the cerebellum through Purkinje neuron axons to affect normal control of movement.