Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS. IntroductionMonocarboxylate transporter 8 (MCT8) is a specific thyroid hormone (TH) transporter that facilitates the passage of the prohormone 3,3′,5,5′-tetraiodothyronine (T4; also known as thyroxine) and the receptor active form, 3,3′,5-triiodothyronine (T3), across the plasma membrane (1). MCT8 is encoded by SLC16A2 (hereafter MCT8) located on human chromosome Xq13.2. Inactivating mutations and deletions in MCT8 result in a distinct clinical picture known as Allan-Herndon-Dudley syndrome (AHDS) (2-5).All affected patients manifest a severe form of psychomotor retardation composed of central hypotonia, spastic tetraplegia, lack of speech development, severe intellectual deficits, and global developmental delays. In addition to the pronounced neurological symptoms, patients exhibit characteristic changes in the serum TH profile, with highly elevated T3 and lowered T4 concentrations. Since 2004, more than 45 families with 125 affected individuals have been reported in the literature, and 1% of cases with the diagnosis of X-linked mental retardation have been estimated to be associated with mutations in MCT8 (6). However, by which pathogenic mechanisms MCT8 deficiency causes AHDS remains largely unknown.MCT8 is present in many organs, such as liver, kidneys, pituitary, and thyroid gland, and is also widely expressed in the CNS. Studies in mouse and human brain tissues revealed MCT8 expression in distinct neuronal populations, with the highest mRNA levels in neo-and allocortical structures (e.g., cerebral cor...
Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels.DOI: http://dx.doi.org/10.7554/eLife.23332.001
Mutations of several genes encoding peroxisomal proteins have been associated with human diseases. Some of these display specific white matter abnormalities in the brain, although the affected proteins are ubiquitously expressed. To better understand the etiology of peroxisomal myelin diseases, we aimed to label these organelles in vivo and in a cell type specific fashion. We had previously shown that in oligodendrocytes and Schwann cells numerous peroxisomes reside in the cytoplasmic channels of "non-compacted" myelin. These organelles are smaller and biochemically distinct from non-myelin peroxisomes. Targeting peroxisomal functions in various cell types of the brain has demonstrated that oligodendroglial peroxisomes are specifically important for long-term integrity of the CNS. To visualize myelin peroxisomes in intact cells and tissues by live imaging, we have generated a novel line of transgenic mice for the expression of fluorescently tagged peroxisomes specifically in myelinating glia. This was achieved by modifying the gene for a photoconvertible mEos2 with a peroxisomal targeting signal type 1 (PTS1) and generating a fusion gene with the myelin-specific Cnp1 promoter. In the brain of resulting transgenic mice, peroxisomes are selectively labeled in oligodendrocytes. In this novel genetic tool, photoconversion of single peroxisomes from green to red fluorescence can be used to monitor the fate of single organelles and to determine the dynamics of PTS1-mediated protein import in the context of myelin diseases that affect peroxisomal functions.
Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal K v 1-channels.
The mTOR (mechanistic target of rapamycin) pathway is a central regulator of cell growth and differentiation. In psoriasis, the mTOR kinase is activated throughout the whole epidermis, with particularly strong activation in the basal proliferating epidermal layer. To date, diseaseintrinsic factors which regulate epidermal mTOR activity are yet to be investigated. Koebnerisin (S100A15) is an innate anti-microbial and immune-modulatory peptide strongly upregulated in the psoriatic epidermis. Our data revealed that the localization of koebnerisin resembles the activation pattern of the mTOR kinase. We hypothesized a functional link and unveiled that koebnerisin was capable of activating mTOR signaling via the PI3-K/Akt cascade in keratinocytes. Functionally koebnerisin conferred a small effect on keratinocyte proliferation, which emphasizes previous results on the minor role of mTOR signaling in regulating epidermal proliferation. Further, koebnerisin induced mTOR activation interfered with the expression of differentiation markers mostly likely via post-transcriptional regulation. Data suggest a functional link between the innate anti-microbial peptide koebnerisin (S100A15) and mTOR signaling for epidermal maturation and emphasize the mTOR network as a therapeutic target in chronic inflammatory diseases in the skin and beyond.
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