Antisense RNA foci in the motor neurons of C9ORF72 -ALS patients are associated with TDP-43 proteinopathy

Abstract GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We and others have proposed that RNA transcribed from the repeat sequence is toxic via sequestration of RNA-binding factors. Both GGGGCC-repeat (sense) and CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as RNA foci, but their relative expression pattern within the CNS and contribution to disease has not been determined. Blinded examination of CNS biosamples from ALS patients with a repeat expansion of C9ORF72 showed that antisense foci are present at a significantly higher frequency in cerebellar Purkinje neurons and motor neurons, whereas sense foci are present at a significantly higher frequency in cerebellar granule neurons. Consistent with this, inclusions containing sense or antisense derived dipeptide repeat proteins were present at significantly higher frequency in cerebellar granule neurons or motor neurons, respectively. Immunohistochemistry and UV-crosslinking studies showed that sense and antisense RNA molecules share similar interactions with SRSF2, hnRNP K, hnRNP A1, ALYREF, and hnRNP H/F. Together these data suggest that, although sense and antisense RNA molecules might be expected to be equally toxic via their shared protein binding partners, distinct patterns of expression in various CNS neuronal populations could lead to relative differences in their contri...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Abstract Stress granules (SGs) are dynamic membraneless compartments composed out of RNA-binding proteins (RBPs) and RNA molecules that assemble temporarily to allow the cell to cope with cellular stress by stalling mRNA translation and moving synthesis towards cytoprotective proteins. Aberrant SGs have become prime suspects in the nucleation of toxic protein aggregation in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Perturbed SG dynamics appears to be mediated by alterations in RNA binding proteins (RBP). Indeed, a growing number of FTD and/or ALS related RBPs coding genes (TDP43, FUS, ...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
This study presents a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways and applies it to the neurodegenerative disease gene C9orf72. A double strand break induced by CRISPR/cas9 in the promoter of C9orf72 is sufficient to induce DNA methylation, and methylation can be precisely targeted through the process of homology directed repair (HDR) via delivery of an in vitro methylated exogenous repair template. Long methylated double stranded DNA templates induce more methylation than shorter templates and with higher efficiency than a dCas9-DNMT3a fusion protein construct....
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by genome tiling array Homo sapiens Source Type: research
This study presents a novel method of targeted DNA methylation that utilizes endogenous DNA double strand break repair pathways and applies it to the neurodegenerative disease gene C9orf72. A double strand break induced by CRISPR/cas9 in the promoter of C9orf72 is sufficient to induce DNA methylation, and methylation can be precisely targeted through the process of homology directed repair (HDR) via delivery of an in vitro methylated exogenous repair template. Long methylated double stranded DNA templates induce more methylation than shorter templates and with higher efficiency than a dCas9-DNMT3a fusion protein construct....
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Methylation profiling by genome tiling array Homo sapiens Source Type: research
ConclusionsIn this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD.
Source: PLoS Medicine - Category: Internal Medicine Authors: Source Type: research
Publication date: Available online 3 October 2019Source: NeuronAuthor(s): Weiwei Cheng, Shaopeng Wang, Zhe Zhang, David W. Morgens, Lindsey R. Hayes, Soojin Lee, Bede Portz, Yongzhi Xie, Baotram V. Nguyen, Michael S. Haney, Shirui Yan, Daoyuan Dong, Alyssa N. Coyne, Junhua Yang, Fengfan Xian, Don W. Cleveland, Zhaozhu Qiu, Jeffrey D. Rothstein, James Shorter, Fen-Biao GaoSummaryHexanucleotide GGGGCC repeat expansion in C9ORF72 is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the aberrant accumulation of dipeptide repeat (DPR)...
Source: Neuron - Category: Neuroscience Source Type: research
Abstract p97, also known as valosin-containing protein or CDC48, is a member of the AAA+ protein family that is highly conserved in eukaryotes. It binds to various cofactors in the body to perform its protein-unfolding function and participates in DNA repair, degradation of subcellular membrane proteins, and protein quality control pathways, among other processes. Its malfunction can lead to many diseases, such as inclusion body myopathy, associated with Paget's disease of bone and/or frontotemporal dementia, amyotrophic lateral sclerosis disease, and others. In recent years, many small molecule inhibitors have be...
Source: Current Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Med Chem Source Type: research
Publication date: Available online 20 September 2019Source: Pharmacological ResearchAuthor(s): Sweta Bawari, Devesh Tewari, Sandro Argüelles, Archana N. Sah, Seyed Fazel Nabavi, Suowen Xu, Rosa Anna Vacca, Seyed Mohammad Nabavi, Samira ShirooieAbstractNeurodegenerative disorders like Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, frontotemporal dementia to prion diseases, Friedreich’s ataxia, hereditary spastic paraplegia and optic atrophy type 1, and behavior disorders like neuropsychiatric, hyperactivity and autism spect...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research
We describe here a case of progressive childhood-onset cerebellar ataxia with vertical supra nuclear gaze palsy with no family history and a normal magnetic resonance imaging (MRI) of brain. The clinical exome sequencing in this patient showed a homozygous mutation in SQSTM1. This case highlights the importance of next-generation sequencing in the diagnosis of inherited ataxia syndromes. SQSTM1 mutation should be considered in the differential diagnosis in a patient with both cerebellar ataxia and ophthalmological manifestations. PMID: 31525130 [PubMed - as supplied by publisher]
Source: Ophthalmic Genetics - Category: Opthalmology Tags: Ophthalmic Genet Source Type: research
CONCLUSIONS: Our results support the consensus that the R47H variant is significantly associated with AD. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases. PMID: 31513029 [PubMed - as supplied by publisher]
Source: Alzheimer Disease and Associated Disorders - Category: Psychiatry Tags: Alzheimer Dis Assoc Disord Source Type: research
The primary role of magnetic resonance imaging (MRI) in routine diagnostic work-up of motor neuron disease patients is currently still largely limited to exclusion of relevant non-degenerative pathologies. We here present an illustrative case of a 63-year-old woman with early stage Frontotemporal-Dementia-Amyotrophic-Lateral-Sclerosis (FTD-ALS) spectrum disorder showing a striking hypointense signal of the cortical band along the precentral gyrus, termed “Motor Band Sign” (MBS). Based on this finding, we analysed the frequency of the MBS in clinical routine MRIs in a large consecutive series of ALS patients (MR...
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Source Type: research
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