C9orf72 and Triplet Repeat Disorder RNAs: G-quadruplex formation, binding to PRC2 and implications for disease mechanisms.

C9orf72 and Triplet Repeat Disorder RNAs: G-quadruplex formation, binding to PRC2 and implications for disease mechanisms. RNA. 2019 May 02;: Authors: Wang X, Goodrich KJ, Conlon EG, Gao J, Erbse AH, Manley JL, Cech TR Abstract Some neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), Fragile X Syndrome, Huntington's Disease, Myotonic Dystrophy, and various ataxias, can be caused by expansions of short nucleic acid sequence repeats in specific genes. A possible disease mechanism involves the transcribed repeat RNA binding an RNA-binding protein (RBP), resulting in its sequestration and thus dysfunction. Polycomb Repressive Complex 2 (PRC2), the histone methyltransferase that deposits the H3K27me3 mark of epigenetically silenced chromatin, binds G-rich RNAs and has especially high affinity for G-quadruplex (G-Q) structures. Here, we find that PRC2 target genes are derepressed and the RNA binding subunit EZH2 largely insoluble in post-mortem brain samples from ALS/FTD patients with C9ORF72 (C9) repeat expansions, leading to the hypothesis that the (G4C2)n repeat RNA might be sequestering PRC2. Contrary to this expectation, we found that C9 repeat RNAs (n = 6 or 10) bind weakly to purified PRC2, and studies with the G-Q specific BG4 antibody and circular dichroism studies both indicated that these C9 RNAs have little propensity to form G-Qs in vitro. Several GC-rich triplet-repeat expansion RNAs also have low...
Source: RNA - Category: Genetics & Stem Cells Authors: Tags: RNA Source Type: research

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Source: Journal of Neurosurgical Sciences - Category: Neurosurgery Tags: J Neurosurg Sci Source Type: research
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Source: Korean Journal of Pediatrics - Category: Pediatrics Tags: Korean J Pediatr Source Type: research
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Source: The American Journal of Geriatric Psychiatry - Category: Psychiatry Tags: Am J Geriatr Psychiatry Source Type: research
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Source: Alzheimer Disease and Associated Disorders - Category: Psychiatry Tags: Alzheimer Dis Assoc Disord Source Type: research
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Source: SafetyLit - Category: International Medicine & Public Health Tags: Age: Elder Adults Source Type: news
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Source: NeuroImage: Clinical - Category: Radiology Source Type: research
Conditions:   Gut Microbiota;   Mild Cognitive Impairment;   Dementia, Alzheimer Type;   Neuroimaging Interventions:   Dietary Supplement: Probiotic supplemented intervention;   Dietary Supplement: Functional foods;   Dietary Supplement: Placebo Sponsors:   XuanwuH 2;   First Hospital of Tsinghua University;   Beijing Normal University Recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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Source: Alzheimer's and Dementia: The Journal of the Alzheimer's Association - Category: Geriatrics Source Type: research
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