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

Interferon-induced immunoproteasomes disturb neuronal metabolism and drive neurodegeneration in multiple sclerosis [RNA_Seq2_IFNG]

Project description:Interferon-induced immunoproteasomes disturb neuronal metabolism and drive neurodegeneration in multiple sclerosis [RNA_Seq2_IFNG]

| PRJNA1174118 | ENA

Interferon-induced immunoproteasomes disturb neuronal metabolism and drive neurodegeneration in multiple sclerosis [RNS_Seq3_Nuclei]

Project description:Interferon-induced immunoproteasomes disturb neuronal metabolism and drive neurodegeneration in multiple sclerosis [RNS_Seq3_Nuclei]

| PRJNA1174119 | ENA

Interferon-induced immunoproteasomes disturb neuronal metabolism and drive neurodegeneration in multiple sclerosis [RNA_Seq1_Proteasome]

Project description:Interferon-induced immunoproteasomes disturb neuronal metabolism and drive neurodegeneration in multiple sclerosis [RNA_Seq1_Proteasome]

| PRJNA1174125 | ENA

Mapping the Molecular Signature of Progressive Multiple Sclerosis [194017]

Project description:Multiple Sclerosis is a complex neurological disorder characterised by inflammation, demyelination, and neurodegeneration of the central nervous system. While treatments exist for relapsing-remitting multiple sclerosis, therapeutic options for the progressive forms remain limited, highlighting the need to understand their distinct pathological mechanisms. To identify subtype specific molecular signatures in patients with multiple sclerosis, bulk RNA sequencing was performed in 90 brain tissue samples from donors with relapsing-remitting, secondary progressive, and primary progressive multiple sclerosis, as well as controls without the disease. This study provides open access to transcriptomic data from multiple sclerosis tissue samples, enabling other researchers to perform independent analyses, validate findings, and generate new hypotheses.

2025-02-26 | GSE290450 | GEO

Mapping the Molecular Signature of Progressive Multiple Sclerosis [197191]

2025-02-26 | GSE290552 | GEO