Mitochondrial control of sleep.

The function of sleep remains one of biology's biggest mysteries. A solution to this problem is likely to come from a better understanding of sleep homeostasis, and in particular of the cellular and molecular processes that sense sleep need and settle sleep debt. Here, we highlight recent work in the fruit fly showing that changes in the mitochondrial redox state of sleep-promoting neurons lie at the heart of a homeostatic sleep-regulatory mechanism.

A potassium channel β-subunit couples mitochondrial electron transport to sleep.

The essential but enigmatic functions of sleep must be reflected in molecular changes sensed by the brain's sleep-control systems. In the fruitfly Drosophila, about two dozen sleep-inducing neurons with projections to the dorsal fan-shaped body (dFB) adjust their electrical output to sleep need, via the antagonistic regulation of two potassium conductances: the leak channel Sandman imposes silence during waking, whereas increased A-type currents through Shaker support tonic firing during sleep. Here we show that oxidative byproducts of mitochondrial electron transport regulate the activity of dFB neurons through a nicotinamide adenine dinucleotide phosphate (NADPH) cofactor bound to the oxidoreductase domain of Shaker's Kβ subunit, Hyperkinetic.

Recurrent Circuitry for Balancing Sleep Need and Sleep.

Sleep-promoting neurons in the dorsal fan-shaped body (dFB) of Drosophila are integral to sleep homeostasis, but how these cells impose sleep on the organism is unknown. We report that dFB neurons communicate via inhibitory transmitters, including allatostatin-A (AstA), with interneurons connecting the superior arch with the ellipsoid body of the central complex. These "helicon cells" express the galanin receptor homolog AstA-R1, respond to visual input, gate locomotion, and are inhibited by AstA, suggesting that dFB neurons promote rest by suppressing visually guided movement.

Control of Cell Shape, Neurite Outgrowth, and Migration by a Nogo-A/HSPG Interaction.

Heparan sulfate proteoglycans (HSPGs) critically modulate adhesion-, growth-, and migration-related processes. Here, we show that the transmembrane protein, Nogo-A, inhibits neurite outgrowth and cell spreading in neurons and Nogo-A-responsive cell lines via HSPGs. The extracellular, active 180 amino acid Nogo-A region, named Nogo-A-Δ20, binds to heparin and brain-derived heparan sulfate glycosaminoglycans (GAGs) but not to the closely related chondroitin sulfate GAGs.

The sphingolipid receptor S1PR2 is a receptor for Nogo-a repressing synaptic plasticity.

Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor.

Upregulation of axon guidance molecules in the adult central nervous system of Nogo-A knockout mice restricts neuronal growth and regeneration.

Adult central nervous system axons show restricted growth and regeneration properties after injury. One of the underlying mechanisms is the activation of the Nogo-A/Nogo receptor (NgR1) signaling pathway. Nogo-A knockout (KO) mice show enhanced regenerative growth in vivo, even though it is less pronounced than after acute antibody-mediated neutralization of Nogo-A.

Nogo-A represses anatomical and synaptic plasticity in the central nervous system.

Nogo-A was initially discovered as a myelin-associated growth inhibitory protein limiting axonal regeneration after central nervous system (CNS) injury. This review summarizes current knowledge on how myelin and neuronal Nogo-A and its receptors exert physiological functions ranging from the regulation of growth suppression to synaptic plasticity in the developing and adult intact CNS.

Neuronal Nogo-A modulates growth cone motility via Rho-GTP/LIMK1/cofilin in the unlesioned adult nervous system.

Nogo-A has been extensively studied as a myelin-associated neurite outgrowth inhibitor in the lesioned adult central nervous system. However, its role in the intact central nervous system has not yet been clarified. Analysis of the intact adult nervous system of C57BL/6 Nogo-A knock-out (KO) versus wild-type (WT) mice by a combined two-dimensional gel electrophoresis and isotope-coded affinity tagging approach revealed regulation of cytoskeleton-, transport-, and signaling growth-related proteins, pointing to regulation of the actin cytoskeleton, the neuronal growth machinery, and in particular the Rho-GTPase/LIMK1/cofilin pathway.