Transcriptional regulators of redox balance and other homeostatic processes with the potential to alter neurodegenerative disease trajectory

Abstract

Diverse neurodegenerative diseases share some common aspects to their pathology, with many showing evidence of disruption to the brain's numerous homeostatic processes. As such, imbalanced inflammatory status, glutamate dyshomeostasis, hypometabolism and oxidative stress are implicated in many disorders. That these pathological processes can influence each other both up- and downstream makes for a complicated picture, but means that successfully targeting one area may have an effect on others. This targeting requires an understanding of the mechanisms by which homeostasis is maintained during health, in order to uncover strategies to boost homeostasis in disease. A case in point is redox homeostasis, maintained by antioxidant defences co-ordinately regulated by the transcription factor Nrf2, and capable of preventing not only oxidative stress but also inflammation and neuronal loss in neurodegenerative disease models. The emergence of other master regulators of homeostatic processes in the brain controlling inflammation, mitochondrial biogenesis, glutamate uptake and energy metabolism raises the question as to whether they too can be targeted to alter disease trajectory.

Keywords: antioxidants; neurodegeneration; oxidative stress; transcription factors.

Figure 1.. Some transcription factors controlling homeostatic gene expression programmes in neurons.

Loss of homeostasis at multiple levels (labelled in black) is a hallmark of a variety of neurological disorders associated with synapse loss, axonal damage or neuronal death. These disorders, which include stroke, traumatic brain injury, Alzheimer's disease, motor neuron disease and the progressive phase of multiple sclerosis, as well as others, have some common features centred on core inter-dependent pathological processes involving loss of glutamate homeostasis and excitotoxicity, inflammation, oxidative stress and metabolic/mitochondrial dysfunction [13,40,55]. These common features contrast with the diverse nature of the pathological triggers (in red). As described in the text, genes whose function is to counter or resolve homeostatic challenges in neurons are under the control of many key transcription factors, labelled here in yellow boxes.

Figure 2.. Some transcription factors controlling homeostatic gene expression programs in astrocytes.

As described in the text, genes whose function is to counter or resolve homeostatic challenges in astrocytes are under the control of many key transcription factors, labelled here in yellow boxes.