Figure 3.

Circadian influences on neurodegenerative protein aggregation. Schematic model to highlight possible intersections between the circadian clock and mechanisms underpinning neurodegenerative protein aggregation. The life-history of benign cytosolic proteins is mapped in green as a series incorporating gene expression, folding, post-translational modifications (here represented by phosphorylation), oxidation and, ultimately, clearance through proteasomal degradation and autophagy. Pro-neurodegenerative mechanisms have been identified at every stage, leading to the aggregation of otherwise soluble proteins and their spreading through prion-like mechanisms. The origins of neurotoxicity are unclear, but presumably involve a gain of toxic function. Significantly, many, if not most, of these physiological and pro-neurodegenerative mechanisms are under circadian regulation. Thus, in addition to neurodegenerative diseases affecting the circadian clock, the circadian clock has the potential to promote (or hinder) disease progression.