scholarly journals MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis

Brain ◽  
2015 ◽  
Vol 139 (1) ◽  
pp. 86-100 ◽  
Author(s):  
Laura MacNair ◽  
Shangxi Xiao ◽  
Denise Miletic ◽  
Mahdi Ghani ◽  
Jean-Pierre Julien ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Lateral Sclerosis

scholarly journals RNA-Binding Proteins in Amyotrophic Lateral Sclerosis and Neurodegeneration

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Scott E. Ugras ◽  
James Shorter
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disease ◽  
Rna Processing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Future Studies ◽  
Inclusion Formation ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is an adult onset neurodegenerative disease, which is universally fatal. While the causes of this devastating disease are poorly understood, recent advances have implicated RNA-binding proteins (RBPs) that contain predicted prion domains as a major culprit. Specifically, mutations in the RBPs TDP-43 and FUS can cause ALS. Cytoplasmic mislocalization and inclusion formation are common pathological features of TDP-43 and FUS proteinopathies. Though these RBPs share striking pathological and structural similarities, considerable evidence suggests that the ALS-linked mutations in TDP-43 and FUS can cause disease by disparate mechanisms. In a recent study, Couthouis et al. screened for protein candidates that were also involved in RNA processing, contained a predicted prion domain, shared other phenotypic similarities with TDP-43 and FUS, and identified TAF15 as a putative ALS gene. Subsequent sequencing of ALS patients successfully identified ALS-linked mutations in TAF15 that were largely absent in control populations. This study underscores the important role that perturbations in RNA metabolism might play in neurodegeneration, and it raises the possibility that future studies will identify other RBPs with critical roles in neurodegenerative disease.

scholarly journals Dysregulation of RNA-Binding Proteins in Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 13 ◽  
Author(s):  
Yuan Chao Xue ◽  
Chen Seng Ng ◽  
Pinhao Xiang ◽  
Huitao Liu ◽  
Kevin Zhang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Lateral Sclerosis

scholarly journals Revealing the Proteome of Motor Cortex Derived Extracellular Vesicles Isolated from Amyotrophic Lateral Sclerosis Human Postmortem Tissues

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1709
Author(s):  
Natasha Vassileff ◽  
Laura J. Vella ◽  
Harinda Rajapaksha ◽  
Mitch Shambrook ◽  
Amirmohammad Nasiri Kenari ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Cortex ◽  
Extracellular Vesicles ◽  
Motor Neurons ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mass Spectrometry Analysis ◽  
Spectrometry Analysis ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the deposition of misfolded proteins in the motor cortex and motor neurons. Although a multitude of ALS-associated mutated proteins have been identified, several have been linked to small extracellular vesicles such as exosomes involved in cell−cell communication. This study aims to determine the proteome of extracellular vesicles isolated from the motor cortex of ALS subjects and to identify novel ALS-associated deregulated proteins. Motor cortex extracellular vesicles (MCEVs) were isolated from human postmortem ALS (n = 10) and neurological control (NC, n = 5) motor cortex brain tissues and the MCEVs protein content subsequently underwent mass spectrometry analysis, allowing for a panel of ALS-associated proteins to be identified. This panel consists of 16 statistically significant differentially packaged proteins identified in the ALS MCEVs. This includes several upregulated RNA-binding proteins which were determined through pathway analysis to be associated with stress granule dynamics. The identification of these RNA-binding proteins in the ALS MCEVs suggests there may be a relationship between ALS-associated stress granules and ALS MCEV packaging, highlighting a potential role for small extracellular vesicles such as exosomes in the pathogenesis of ALS and as potential peripheral biomarkers for ALS.

scholarly journals Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2572-2580 ◽  
Author(s):  
Giulia E Tyzack ◽  
Raphaelle Luisier ◽  
Doaa M Taha ◽  
Jacob Neeves ◽  
Miha Modic ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Nuclear Export ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Spinal Cord Tissue ◽  
Cytoplasmic Inclusions ◽  
Sporadic Als ◽  
Lateral Sclerosis ◽  
Fus Protein

Abstract Mutations causing amyotrophic lateral sclerosis (ALS) clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins, which form pathological cytoplasmic inclusions in this context. However, the possibility that wild-type RNA binding proteins mislocalize without necessarily becoming constituents of cytoplasmic inclusions themselves remains relatively unexplored. We hypothesized that nuclear-to-cytoplasmic mislocalization of the RNA binding protein fused in sarcoma (FUS), in an unaggregated state, may occur more widely in ALS than previously recognized. To address this hypothesis, we analysed motor neurons from a human ALS induced-pluripotent stem cell model caused by the VCP mutation. Additionally, we examined mouse transgenic models and post-mortem tissue from human sporadic ALS cases. We report nuclear-to-cytoplasmic mislocalization of FUS in both VCP-mutation related ALS and, crucially, in sporadic ALS spinal cord tissue from multiple cases. Furthermore, we provide evidence that FUS protein binds to an aberrantly retained intron within the SFPQ transcript, which is exported from the nucleus into the cytoplasm. Collectively, these data support a model for ALS pathogenesis whereby aberrant intron retention in SFPQ transcripts contributes to FUS mislocalization through their direct interaction and nuclear export. In summary, we report widespread mislocalization of the FUS protein in ALS and propose a putative underlying mechanism for this process.

RNA binding proteins and the pathological cascade in ALS/FTD neurodegeneration

2017 ◽  
Vol 9 (415) ◽  
pp. eaah5436 ◽  
Author(s):  
Daisuke Ito ◽  
Mami Hatano ◽  
Norihiro Suzuki
Keyword(s):  
Quality Control ◽  
Amyotrophic Lateral Sclerosis ◽  
Molecular Basis ◽  
Binding Proteins ◽  
Rna Binding ◽  
Protein Quality ◽  
Rna Binding Proteins ◽  
Therapeutic Strategies ◽  
Related Proteins ◽  
Lateral Sclerosis

Advanced genetic approaches have accelerated the identification of causative genes linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the disease-related proteins encoded by these genes form aggregates in the cellular machineries that regulate RNA and protein quality control in cells. Cross-talk among the signaling pathways governing these machineries leads to pathological cascades mediated by the accumulation of mutant RNA binding proteins. We outline the molecular basis of ALS and FTD pathogenesis and discuss the prospects for therapeutic strategies to treat these diseases.

scholarly journals Molecular Network Analysis Suggests a Logical Hypothesis for the Pathological Role of C9orf72 in Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

2014 ◽  
Vol 6 ◽  
pp. JCNSD.S18103 ◽  
Author(s):  
Jun-Ichi Satoh ◽  
Yoji Yamamoto ◽  
Shouta Kitano ◽  
Mika Takitani ◽  
Naohiro Asahina ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Motor Neurons ◽  
Rna Processing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cytoskeletal Dynamics ◽  
Lateral Sclerosis

Background Expanded GGGGCC hexanucleotide repeats, ranging from hundreds to thousands in number, located in the noncoding region of the chromosome 9 open reading frame 72 ( C9orf72) gene represent the most common genetic abnormality for familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (abbreviated as C9ALS). Currently, three pathological mechanisms, such as haplo insufficiency of C9orf72, formation of nuclear RNA foci composed of sense and antisense repeats, and accumulation of unconventionally transcribed dipeptide-repeat (DPR) proteins, are proposed for C9ALS. However, at present, the central mechanism underlying neurodegeneration in C9ALS remains largely unknown. Methods By using three distinct pathway analysis tools of bioinformatics, we studied molecular networks involved in C9ALS pathology by focusing on C9orf72 omics datasets, such as proteome of C9orf72 repeat RNA-binding proteins, transcriptome of induced pluripotent stem cells (iPSC)-derived motor neurons of patients with C9ALS, and transcriptome of purified motor neurons of patients with C9ALS. Results We found that C9orf72 repeat RNA-binding proteins play a crucial role in the regulation of post-transcriptional RNA processing. The expression of a wide range of extracellular matrix proteins and matrix metalloproteinases was reduced in iPSC-derived motor neurons of patients with C9ALS. The regulation of RNA processing and cytoskeletal dynamics is disturbed in motor neurons of patients with C9ALS in vivo. Conclusions Bioinformatics data mining approach suggests a logical hypothesis that C9orf72 repeat expansions that deregulate post-transcriptional RNA processing disturb the homeostasis of cytoskeletal dynamics and remodeling of extracellular matrix, leading to degeneration of stress-vulnerable neurons in the brain and spinal cord of patients with C9ALS.

Sign in / Sign up

Export Citation Format

Share Document