Circadian clocks and neurodegenerative diseases: time to aggregate? ^☆

Highlights

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  Neurodegenerative diseases are characterised by disordered sleep/wake patterns.

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  Aggregation of soluble proteins is the canonical molecular motif of neurodegeneration.

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  Local circadian clocks direct processes influencing pro-neurodegenerative aggregation.

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  Thus, circadian/sleep–wake timing and neurodegeneration are reciprocally dependent.

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  Revealing the feedback between clocks and neurodegeneration may suggest new therapies.

Abstract

The major neurodegenerative diseases are characterised by a disabling loss of the daily pattern of sleep and wakefulness, which may be reflective of a compromise to the underlying circadian clock that times the sleep cycle. At a molecular level, the canonical property of neurodegenerative diseases is aberrant aggregation of otherwise soluble neuronal proteins. They can thus be viewed as disturbances of proteostasis, raising the question whether the two features — altered daily rhythms and molecular aggregation — are related. Recent discoveries have highlighted the fundamental contribution of circadian clocks to the correct ordering of daily cellular metabolic cycles, imposing on peripheral organs such as the liver a strict programme that alternates between anabolic and catabolic states. The discovery that circadian mechanisms are active in local brain regions suggests that they may impinge upon physiological and pathological elements that influence pro-neurodegenerative aggregation. This review explores how introducing the dimension of circadian time and the circadian clock might refine the analysis of aberrant aggregation, thus expanding our perspective on the cell biology common to neurodegenerative diseases.