Project description:RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Recently, we demonstrated extensive RNA oxidation within the neurons in multiple sclerosis (MS) brain. In this report we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) mRNA is one such transcript, whose translated product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite essential for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in reduction in its cognate protein, thus lowering NAA level. This assertion is directly supported by our studies on a model cellular system, an MS animal model and postmortem human MS brain. Reduced NAA level in the brain could hamper myelin synthesis causing neuronal damage, which results in MS neurodegeneration. Overall, this work provides a framework for mechanistic understanding of the link between RNA oxidation and neurodegenerative diseases.

2020-01-28 | GSE144294 | GEO

Bassoon proteinopathy drives neurodegeneration in multiple sclerosis

Project description:During the course of multiple sclerosis (MS), inflammatory insults drive neuro-axonal loss and disability progression. However, pathways that guide neurons toward survival or death during central nervous system (CNS) inflammation are largely unexplored. Here we show that somatic deposition of the presynaptic protein bassoon (Bsn) in inflamed neurons directly contributes to neurodegeneration in MS. By comparing neuron-specific RNA-seq of healthy mice to mice undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identified key components of neurodegenerative pathways, including reduced mitochondrial ATP synthesis and increased protein catabolism. These changes were accompanied by neuronal induction and deposition of the intrinsically disordered protein Bsn in both EAE and in patients with MS. Somatic Bsn also accumulated in Bsn-overexpressing Neuro-2a (N2a) cells and single cell RNA-seq revealed dose-dependent repression of energy metabolism and induction of the unfolded protein response, reminiscent of our in vivo findings. Furthermore, Bsn overexpression in N2a cells or in Drosophila melanogaster neurons led to decreased survival and shortened lifespan, respectively. Conversely, genetic disruption of Bsn in mice was neuroprotective, with reduced neuro-axonal injury and clinical disability during EAE, establishing a toxic gain-of-function of Bsn during CNS inflammation. Our study provides systemic insights into neuronal responses to inflammation and identifies protein accumulation as a generic pathomechanism uniting primary and inflammatory neurodegeneration. Moreover, it offers a new explanation and possible treatment strategy to halt disability progression in MS, irrespective of immunotherapies.

2019-04-03 | GSE104899 | GEO

Multiple sclerosis and EAE

Project description:Multiple sclerosis and EAE

| PRJNA391342 | ENA

Multiple Sclerosis

Project description:Elevated genetic risk for multiple sclerosis originated in Steppe Pastoralist populations

| PRJEB65098 | ENA

Neuronal Methylome in Multiple Sclerosis

Project description:Neuronal Methylome in Multiple Sclerosis

| PRJNA489474 | ENA

International Multiple Sclerosis Genomics Consortium (IMSGC) Genome Wide Association Study of Multiple Sclerosis

Project description:International Multiple Sclerosis Genomics Consortium (IMSGC) Genome Wide Association Study of Multiple Sclerosis

| PRJNA75425 | ENA

Transcription signature of Multiple Sclerosis

Project description:This SuperSeries is composed of the following subset Series: GSE17393: Transcription signature of Multiple Sclerosis in peripheral blood mononuclear cells. GSE17409: Pregnancy changes expression in peripheral blood mononuclear cells of healthy donors GSE17410: Pregnancy changes expression in peripheral blood mononuclear cells of Multiple Sclerosis (MS) patients Refer to individual Series

2010-01-10 | E-GEOD-17449 | biostudies-arrayexpress

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