Unknown,Transcriptomics,Genomics,Proteomics

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Reduced sialylation triggers complement c3-mediated neuronal loss in aging mice

ABSTRACT: Mice heterozygous for the bifunctional enzyme glucosamine-2-epimerase/N-acetylmannosamine kinase (GNE+/-), which is essential for sialic acid biosynthesis, showed reduced gne transcription and sialylation in different brain regions. We found synapse loss in the hippocampus of GNE+/- mice at 6 months followed by a gradual loss of neurons in the hippocampus and substantia nigra at 12 months. Moreover, GNE+/- mice showed reduced arborization of microglia already at 6 months. A transcriptomic analysis revealed only minor inflammatory changes with slightly increased Interleukin 1β levels, indicating a homeostatic removal of synapses and neurons. Crossbreeding with complement component 3-deficient mice rescued the early onset loss of neurons and synapses in the GNE+/- mice. Thus, an intact sialic acid covered glycocalyx plays an essential role in maintaining brain homeostasis. Even a minor reduction in the sialic acid level leads to reduced microglial arborization and complement-mediated loss of neurons and synapses.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Aurelien Ginolhac

PROVIDER: E-MTAB-7790 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:GNE Myopathy is a rare, recessively inherited neuromuscular worldwide disorder, caused by a spectrum of bi-allelic mutations in the human GNE gene. GNE encodes a bi-functional enzyme responsible for the rate-limiting step of sialic acid biosynthesis pathway. However, the process in which GNE mutations lead to the development of a muscle pathology is not clear yet. Cellular and mouse models for GNE Myopathy established to date have not been informative. Further, additional GNE functions in muscle have been hypothesized. In these studies, we aimed to investigate gne functions using zebrafish genetic and transgenic models, and characterized them using macroscopic, microscopic, and molecular approaches. We first established transgenic zebrafish lineages expressing the human GNE cDNA carrying the M743T mutation, driven by the zebrafish gne promoter. These fish developed entirely normally. Then, we generated a gne knock-out (KO) fish using the CRISPR/Cas9 methodology. These fish died 8-10 days post-fertilization (dpf), but a phenotype appeared less than 24 hours before death and included progressive body axis curving, deflation of the swim bladder and decreasing movement and heart rate. However, muscle histology uncovered severe defects, already at 5 dpf, with compromised fiber organization. Sialic acid supplementation did not rescue the larvae from this phenotype nor prolonged their lifespan. To have deeper insights into the potential functions of gne in zebrafish, RNA sequencing was performed at 3 time points (3, 5, and 7 dpf). Genotype clustering was progressive, with only 5 genes differentially expressed in gne KO compared to gne WT siblings at 3 dpf. Enrichment analyses of the primary processes affected by the lack of gne also at 5 and 7 dpf point to the involvement of cell cycle and DNA damage/repair processes in the gne KO zebrafish. Thus, we have established a gne KO zebrafish lineage and obtained new insights into gne functions. This is the only model where GNE can be related to clear muscle defects, thus the only animal model relevant to GNE Myopathy to date. Further elucidation of gne precise mechanism-of-action in these processes could be relevant to GNE Myopathy and allow the identification of novel therapeutic targets.

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Reduced sialylation triggers complement c3-mediated neuronal loss in aging mice

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