Unknown,Transcriptomics,Genomics,Proteomics

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Expression data for 2-month-old wild type and Tfam-SCKO (MPZ-Tfam KO) sciatic nerves

ABSTRACT: Gene expression analysis of 2-month-old Ctrl and Tfam-SCKO mice. At this age mitochondrial function is disrupted in the Schwann cells of Tfam-SCKO mice ,but their nerves display only very limited pathology. Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells, SCs) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response through actions of heme-regulated inhibitor kinase (HRI), and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines, an intermediate of fatty acid b-oxidation. Importantly, we show that acylcarnitines are released from SCs and induce axonal degeneration. A maladaptive integrated stress response as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies. Total RNA samples were prepared by isolating and pooling RNA from three different 2-month-old MPZ-Tfam KO and Ctrl mice. 2 replicates per genotype were used in this experiment and they were prepared entirely independently.

ORGANISM(S): Mus musculus

SUBMITTER: Nobish Varghese

PROVIDER: E-GEOD-44605 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The core component of the class III phosphatidylinositol 3-kinase complex, Beclin 1, takes part in different protein networks, thus switching its role from inducing autophagy to regulating autophagosomal maturation and endosomal trafficking. While assessed in neurons, astrocytes and microglia, its role was far less investigated in myelinating glia, including Schwann cells (SCs), responsible for peripheral nerve myelination. Remarkably, the dysregulation in endosomal trafficking is emerging as a pathophysiological mechanism underlying peripheral neuropathies, such as demyelinating Charcot-Marie-Tooth diseases. By knocking out Beclin 1 in SCs we here generated a novel mouse model (Becn1 cKO), developing a severe and progressive neuropathy, accompanied by involuntary tremors, body weight loss and premature death. Ultrastructural analysis revealed abated myelination and SCs displaying enlarged cytoplasm with progressive accumulation of intracellular vesicles. Transcriptomic and histological analysis from sciatic nerves of 10-day and 2-month-old mice revealed pro-mitotic gene deregulation and increased SCs proliferation at both stages with axonal loss and increased immune infiltration in adults, well reflecting the progressive motor and sensory functional impairment that characterizes Becn1 cKO mice, compared to controls. Our study establishes a further step in understanding key mechanisms in SC development and points to Beclin 1 and its regulated pathways as targets for demyelinating CMT forms. A novel conditional gene knockout was generated to investigate the role that Beclin 1 exerts in Schwann cells and in myelination. The newly generated mouse line resulted in a model for severe and progressive peripheral neuropathy. Together with defective myelination, we described radial sorting defects, motor and sensory neuron impairments, immune infiltrate in adults and a huge transcripts deregulation. The emerged deregulated signalling pathways highlighted how Beclin 1 is able to coordinate integrated signaling pathways essential for Schwann cell maturation and nerve development and homeostasis.

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Expression data for 2-month-old wild type and Tfam-SCKO (MPZ-Tfam KO) sciatic nerves

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