Sense and antisense RNA are not toxic in Drosophila models of C9orf72 -associated ALS/FTD

AbstractA GGGGCC hexanucleotide repeat expansion in theC9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Neurodegeneration may occur via transcription of the repeats into inherently toxic repetitive sense and antisense RNA species, or via repeat-associated non-ATG initiated translation (RANT) of sense and antisense RNA into toxic dipeptide repeat proteins. We have previously demonstrated that regular interspersion of repeat RNA with stop codons prevents RANT (RNA-only models), allowing us to study the role of repeat RNA in isolation. Here we have created novel RNA-onlyDrosophila models, including the first models of antisense repeat toxicity, and flies expressing extremely large repeats, within the range observed in patients. We generated flies expressing ~  100 repeat sense or antisense RNA either as part of a processed polyadenylated transcript or intronic sequence. We additionally createdDrosophila expressing>  1000 RNA-only repeats in the sense direction. When expressed in adultDrosophila neurons polyadenylated repeat RNA is largely cytoplasmic in localisation, whilst intronic repeat RNA forms intranuclear RNA foci, as does>  1000 repeat RNA, thus allowing us to investigate both nuclear and cytoplasmic RNA toxicity. We confirmed that these RNA foci are capable of sequestering endogenousDrosophila RNA-binding proteins, and that the production of dipeptide proteins (poly-glycine –proline, a...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

Related Links:

Valosin-containing protein (VCP) is a ubiquitous protein, being broadly expressed in several human body systems [1]. More than 45 missense mutations in the VCP gene have been associated with several disease conditions, collectively known as ‘multisystem proteinopathies’: these include early-onset Paget disease of the bone (PDB), myopathy with rimmed vacuoles or inclusion body myopathy (IBM), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) [2, 3].. Myopathy is the most common clinical feature of these conditio ns, mainly affecting proximal muscles.
Source: Journal of the Neurological Sciences - Category: Neurology Authors: Tags: Letter to the Editor Source Type: research
CONCLUSIONS: The MND-FTD patients frequently displayed a distinctive motor pattern characterized by weakness and atrophy in distal upper limb muscles and dysphagia, with no or little spreading to other regions. These features may help to define specific subgroups of patients, which is important with regard to clinical management, outcome, and research. PMID: 29886477 [PubMed - as supplied by publisher]
Source: Dementia and Geriatric Cognitive Disorders - Category: Psychiatry Tags: Dement Geriatr Cogn Disord Source Type: research
Conclusions: The MND-FTD patients frequently displayed a distinctive motor pattern characterized by weakness and atrophy in distal upper limb muscles and dysphagia, with no or little spreading to other regions. These features may help to define specific subgroups of patients, which is important with regard to clinical management, outcome, and research.Dement Geriatr Cogn Disord 2018;45:220 –231
Source: Dementia and Geriatric Cognitive Disorders - Category: Geriatrics Source Type: research
AbstractAimTo investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis –frontotemporal dementia (ALS–FTD) spectrum of diseases.MethodsComprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n = 27) and ALS–FTD (n = 12). Clinical features, Addenbrooke’s Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented. Motor cortex excitabilit...
Source: Journal of Neurology - Category: Neurology Source Type: research
Conclusions: [18F]FL2-b is a blood brain barrier permeable metal-protein aggregate binding agent. Autoradiography results from our previous work and the current study demonstrate increased uptake of the radiotracer in AD, ALS and DLB brain sections when compared to control brain sections. This data suggests to bind to metal-protein aggregates [18F]FL2-b in those diseases and further work is underway to evaluate its potential for estimating amyloid of TDP-43 aggregate burden and imaging disease progression in these neurodegenerative disorders. References: (1) Brooks, A.; Jackson, I.; Scott, P. J. Nucl. Med. 2017, 58 (supple...
Source: Journal of Nuclear Medicine - Category: Nuclear Medicine Authors: Tags: Probes for Neuroimaging II Source Type: research
Abstract Expansion of a hexanucleotide repeat (HRE), GGGGCC, in the C9ORF72 gene is recognized as the most common cause of familial amyotrophic lateral sclerosis (FALS), frontotemporal dementia (FTD) and ALS-FTD, as well as 5-10% of sporadic ALS. Despite the location of the HRE in the non-coding region (with respect to the main C9ORF72 gene product), dipeptide repeat proteins (DPRs) that are thought to be toxic are translated from the HRE in all three reading frames from both the sense and antisense transcript. Here, we identified a CUG translation initiation codon that has a good Kozak consensus sequence as the t...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
Contributors : Tassa K Saldi   ; Patrick Gonzales ; Alfonso Garrido-Lecca ; Vishantie Dostal ; Christine M Roberts ; Lenoard Petrucelli ; Christopher D LinkSeries Type : Expression profiling by high throughput sequencing ; Genome binding/occupancy profiling by high throughput sequencing ; OtherOrganism : Caenorhabditis elegansTDP-1 is the  C. elegans ortholog of mammalian TDP-43, which is strongly implicated in the etiology of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). We discovered that deletion of the tdp-1 gene results in enhanced transcriptional gene silencing leadin...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Genome binding/occupancy profiling by high throughput sequencing Other Caenorhabditis elegans Source Type: research
Conclusion: The complex molecular underpinnings of these disorders are currently elusive. Despite heterogeneous clinical and pathological expressions, common features have been recognized in many NDs which provide evidence of their convergence. PMID: 29755292 [PubMed]
Source: Current Genomics - Category: Genetics & Stem Cells Tags: Curr Genomics Source Type: research
Abstract TAR DNA-binding protein-43 KDa (TDP-43) and fused in sarcoma (FUS) as the defining pathological hallmarks for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coupled with ALS-FTD-causing mutations in both genes, indicate that their dysfunctions damage the motor system and cognition. On the molecular level, TDP-43 and FUS participate in the biogenesis and metabolism of coding and noncoding RNAs as well as in the transport and translation of mRNAs as part of cytoplasmic mRNA-ribonucleoprotein (mRNP) granules. Intriguingly, many of the RNA targets of TDP-43 and FUS are involved ...
Source: Neural Plasticity - Category: Neurology Authors: Tags: Neural Plast Source Type: research
Frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese patients with amyotrophic lateral sclerosis. Neurobiol Aging. 2018 May 14;: Authors: Gromicho M, Pinto S, Gisca E, Pronto-Laborinho AC, de Carvalho M Abstract Mutation frequency of the 2 main amyotrophic lateral sclerosis (ALS)-related genes, C9orf72 and SOD1, varies considerably across the world. We analyzed those genes in a large population of Portuguese ALS patients (n = 371) and recorded demographic and clinical features. Familial ALS (FALS) was disclosed in 11.6% of patients. Mutations in either S...
Source: Neurobiology of Aging - Category: Geriatrics Authors: Tags: Neurobiol Aging Source Type: research
More News: ALS | Brain | Dementia | Genetics | Neurology | Study | Toxicology