Summary: New research from the University of Oxford links oxidative stress—the same cellular process implicated in ageing and neurodegenerative disease—with the brain mechanisms that trigger sleep. The study shows oxidative stress activates specific sleep-regulating neurons, a finding that could inform future treatments for insomnia and other sleep disorders.
Source: University of Oxford
Oxford researchers identify a molecular link between sleep regulation and ageing-related oxidative stress
Scientists at the University of Oxford report in the journal Nature that oxidative stress can drive sleep by altering the chemistry of a potassium channel subunit found in sleep-controlling neurons. Oxidative stress, a byproduct of normal cellular energy production, is widely associated with ageing and degenerative diseases. This new work ties those metabolic processes directly to the neural switching mechanisms that determine sleep and wakefulness.
The research, led by Professor Gero Miesenböck of Oxford’s Centre for Neural Circuits and Behaviour, studied sleep regulation in the fruit fly Drosophila. Fruit flies were the organism that first revealed the molecular basis of circadian rhythms, and their sleep-control neurons share molecular features with neurons in other animals, including mammals.
Previous work from the Miesenböck lab showed that a small set of sleep-inducing neurons acts like a binary switch: when electrically active, flies sleep; when silent, flies are awake. In the current study, the team asked what flips that switch and how signals that reflect the animal’s metabolic state influence that decision.
Dr. Seoho Song, one of the lead authors, explained that their earlier work pointed to two potassium conductances that balance neuronal activity: the Sandman leak channel enforces silence during wakefulness, while A-type currents carried by the Shaker channel promote firing associated with sleep. The question became: what drives current to flow preferentially through Shaker?
The researchers discovered the key in a small molecule bound to the potassium channel’s regulatory subunit. The Shaker channel associates with a β-subunit (known as Hyperkinetic) that binds a nicotinamide adenine dinucleotide phosphate cofactor—NADPH. The cofactor cycles between reduced (NADPH) and oxidized (NADP+) states depending on the level of oxidative stress within the neuron. That chemical state alters the behavior of the Shaker channel: oxidation of the cofactor slows inactivation of the A-type current, increasing neuronal firing and thereby promoting sleep.
In striking experimental demonstrations, manipulating the chemical state of the Shaker-bound cofactor was sufficient to change sleep behavior. A light-triggered conversion of the cofactor pushed flies into sleep, showing that the neuronal mechanism can be rapidly and causally controlled by shifting the redox state of the bound molecule.
Lead author Dr Anissa Kempf, a postdoctoral fellow in the Miesenböck group, described the system with an analogy: the Shaker channel’s conducting portion is like a balloon and the cofactor sits beneath it like a gondola. When the cofactor’s chemistry changes in response to oxidative stress, it alters the channel’s electrical properties and thus the sleep-control neurons’ activity.
Professor Miesenböck notes that these findings offer a new therapeutic direction. Current sleeping medications can carry side effects such as confusion, memory problems, and risk of dependence. Drugs designed to modulate the redox state of the Shaker-associated cofactor or to influence KVβ substrates could potentially promote sleep with a different side-effect profile by targeting a biochemical record of sleep debt rather than broadly suppressing brain activity.
Beyond therapeutics, the study establishes a mechanistic connection among energy metabolism, oxidative stress, and sleep—three processes long associated independently with lifespan, ageing, and neurodegenerative disease. The results also provide a plausible explanation for observations that chronic sleep loss shortens life expectancy: accumulated oxidative stress may alter the sleep-control circuitry itself.
Source:
University of Oxford
Media Contacts:
Stuart Gillespie – University of Oxford
Image Source:
The image is in the public domain.
Original Research: Closed access
“A potassium channel β-subunit couples mitochondrial electron transport to sleep”
Anissa Kempf, Seoho M. Song, Clifford B. Talbot & Gero Miesenböck
Nature (2019) doi: 10.1038/s41586-019-1034-5
Abstract summary
The study shows that in Drosophila, a small population of sleep-promoting neurons adjusts electrical output in response to the balance of two potassium conductances. Oxidative byproducts of mitochondrial electron transport alter a nicotinamide adenine dinucleotide phosphate cofactor bound to the KVβ subunit Hyperkinetic, shifting it from NADPH to NADP+. This oxidation modifies the Shaker A-type current, increasing action potential frequency and promoting sleep. The findings mechanistically connect energy metabolism, oxidative stress, and sleep, and identify KVβ cofactors as potential targets for sleep-regulating drugs.