Summary Oligodendroglia support axon survival and function through mechanisms independent of myelination and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been hypothesized. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and utilization. We show the most abundant lactate transporter in the CNS, monocarboxylate transporter 1 (MCT1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and mouse models of, amyotrophic lateral sclerosis (ALS), suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.

Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence and MCT1 tdTomato BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves in MCT1 heterozygous null mice are crushed and peripheral nerve regeneration quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly through failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush.

Cholangiocyte proliferation is one of the hallmarks of the response to cholestatic injury. We previously reported that the winged helix transcription factor Foxl1 is dramatically induced in cholangiocytes following bile duct ligation. In this study, we investigated the function of Foxl1 in the bile duct ligation model of cholestatic liver injury in Foxl1 À/À and control mice. We found that Foxl1 À/À livers exhibit an increase in parenchymal necrosis, significantly impaired cholangiocyte and hepatocyte proliferation, and failure to expand bile ductular mass. Wnt3a and Wnt7b expression was decreased in the livers of Foxl1 À/À mice along with reduced expression of the b-catenin target gene Cyclin D1 in Foxl1 À/À cholangiocytes. These results show that Foxl1 promotes liver repair after bile-duct-ligation-induced liver injury through activation of the canonical wnt/b-catenin pathway.

Intrathecal delivery of gene therapeutics is a route of administration that overcomes several of the limitations that plague current immunosuppressive treatments for autoimmune diseases of the central nervous system (CNS). Here we report intrathecal delivery of small amounts (3 μg) of plasmid DNA that codes for an immunomodulatory fusion protein, OX40-TRAIL, comprised of OX40, a tumor necrosis factor receptor, and tumor necrosis factor related apoptosis inducing ligand (TRAIL). This DNA was delivered in a formulated nucleic acid-lipid complex (lipoplex) with an asymmetric two-chain cationic lipid myristoyl (14:0) and lauroyl (12:1) rosenthal inhibitor–substituted compound (MLRI) formed from the tetraalkylammonium glycerol–based compound N-(1-(2,3-dioleoyloxy)-propyl-N-1-(2-hydroxy)ethyl)-N,N-dimethyl ammonium iodide. Delivery and expression in the CNS of OX40-TRAIL in the mouse prior to onset of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, decreased the severity of clinical disease. We believe this preclinical demonstration of rapid, widespread, and biologically therapeutic nonviral gene delivery to the CNS is important in further development of clinical lipid-based therapeutics for CNS disorders.