Endogenous histidine peptides are physiological antioxidants that prevent oligodendrocyte cell death and myelin loss in vivo.

Histidine dipeptides (HDs) are synthesized in brain oligodendrocytes by carnosine synthase (carns1), but their role is unknown. Using metabolomics and in vivo experiments with both constitutive and oligodendrocyte-selective carns1-KO mouse models, we found that HDs are critical for oligodendrocyte survival and protect against oxidative stress. Carns1-KO mouse models had lower numbers of mature oligodendrocytes, increased lipid peroxidation, and behavioral changes. Cuprizone administration, which increases reactive oxygen species in vivo, resulted in higher oligodendrocyte death, demyelination, axonal alterations, and oxidative damage in the corpus callosum of carns1-KO mice. Gliosis and oxidative damage by cuprizone were prevented by pretreatment with the antioxidant N-acetylcysteine. NADPH levels were increased threefold in the brains of carns1-KO mice as an antioxidant response to oxidative stress through acceleration of the pentose phosphate pathway (PPP). This was due to overexpression of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Likewise, expression of NAD kinase, the biosynthetic enzyme for NADP+, and NAMPT, which replenishes the NAD+ pool, was higher in carns1-KO mice brains than in controls. Our observations suggest that HDs cell-autonomously protect oligodendrocytes from oxidative stress, with implications for demyelinating diseases.

A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.

Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum, and microcephaly in children. SLC1A4 catalyzes obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models, including a constitutive Slc1a4-KO mouse, a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E), and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L-serine transporter at the BBB and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids in the brain, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioral impairments. Prenatal and early postnatal oral administration of L-serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioral changes. Administration of L-serine till the second postnatal week also normalized brain weight in Slc1a4-E256 K mice. Our observations suggest that the transport of "non-essential" amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We proposed that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB required for optimal brain growth and leads to a metabolic microcephaly, which may be amenable to treatment with L-serine.

Impairment of serine transport across the blood-brain barrier by deletion of Slc38a5 causes developmental delay and motor dysfunction.

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. Slc38a5-KO pups exhibit motor impairments that are affected by the administration of L-serine at concentrations that replenish the serine pool in the brain. Our results highlight a critical role of Slc38a5 in supplying L-serine via the BBB for proper brain development.

P38α MAPK coordinates the activities of several metabolic pathways that together induce atrophy of denervated muscles.

Physiological or pathological muscle disuse/inactivity or loss of the neural-muscular junction cause muscle atrophy. Atrophy-inducing conditions cause metabolic oxidative stress in the muscle tissue, activation of the ubiquitin-proteasome and of the autophagosome-lysosome systems, enhanced removal of the damaged proteins and organelles, and loss of muscle mass and strength. The signaling pathways that control these catabolic processes are only partially known. In this study, we systematically analyzed the role of p38α mitogen-activated protein kinase (MAPK) in denervation-mediated atrophy. Mice with attenuated activity of p38α (p38AF ) are partially protected from muscle damage and atrophy. Denervated (Den) muscles of these mutant mice exhibit reduced signs of oxidative stress, decreased unfolded protein response and lower levels of ubiquitinated proteins relative to Den muscles of control mice. Further, whereas autopahagy flux is inhibited in Den muscles of control mice, Den muscles of p38AF mice maintain normal level of autophagy flux. Last, muscle denervation affects differently the energy metabolism of muscles in normal and mutant mice; whereas denervation appears to increase mitochondrial oxidative metabolism in control mice, it elevates anaerobic glycolytic metabolism in p38AF mice. Our results indicate, therefore, that attenuation of p38α activity in mice protects Den muscles by reducing oxidative stress, lowering protein damage and improving the clearance of damaged mitochondria by autophagy.