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

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In this study, we found that TXNIP deficiency induces accelerated senescent phenotypes of mouse embryonic fibroblast (MEF) cells under high glucose condition and that the induction of cellular ROS or AKT activation is critical for cellular senescence. Our results also revealed that TXNIP inhibits AKT activity by a direct interaction, which is upregulated by high glucose and H2O2 treatment. In addition, TXNIP knockout mice exhibited an increase in glucose uptake and aging-associated phenotypes including a decrease in energy metabolism and induction of cellular senescence and aging-associated gene expression. We propose that...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
As the amyloid cascade hypothesis of Alzheimer's disease has it, the condition begins with growing levels of amyloid-β in the brain. The amyloid forms solid deposits with a surrounding halo of harmful biochemistry, degrading the function of nearby cells. Perhaps this is caused by failing drainage of cerebrospinal fluid, perhaps by the innate immune response to persistent infections, perhaps by other mechanisms such as the age-related failure of the immune system to clear up molecular waste as aggressively as it should. The amyloid sets the stage for mild cognitive impairment and the later deposition of altered forms o...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs
Publication date: 6 September 2018Source: Cell, Volume 174, Issue 6Author(s): Haiyang Yu, Don W. ClevelandPartial loss of TANK-binding kinase 1 (TBK1) causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Xu et al. identify the role of TBK1 in suppressing neuroinflammation and apoptosis by its inhibition of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and elucidate how aging and genetic susceptibility together cause neuroinflammation.
Source: Cell - Category: Cytology Source Type: research
We examined the relationships (Pearson correlations) between NFL-CSF levels and demographic (age, gender) and clinical (CAG repeat number, disease burden, UHDRS motor, behavioural, functional total scores and NPI scale) variables. All the participants gave their signed consent for the procedure. Results Demographic, clinical data and NFL-CSF levels of all participants are shown in Table 1. NFL-CSF results were significantly higher in all HD subjects [5014.4 (1557.3) ng/l] as compared to controls [331.4 (200.2) ng/l] (p
Source: PLOS Currents Huntington Disease - Category: Neurology Authors: Source Type: research
Publication date: Available online 23 August 2018Source: CellAuthor(s): Daichao Xu, Taijie Jin, Hong Zhu, Hongbo Chen, Dimitry Ofengeim, Chengyu Zou, Lauren Mifflin, Lifeng Pan, Palak Amin, Wanjin Li, Bing Shan, Masanori Gomi Naito, Huyan Meng, Ying Li, Heling Pan, Liviu Aron, Xian Adiconis, Joshua Z. Levin, Bruce A. Yankner, Junying YuanSummaryAging is a major risk factor for both genetic and sporadic neurodegenerative disorders. However, it is unclear how aging interacts with genetic predispositions to promote neurodegeneration. Here, we investigate how partial loss of function of TBK1, a major genetic cause for amyotrop...
Source: Cell - Category: Cytology Source Type: research
(Harvard Medical School) Harvard Medical School researchers have discovered a molecular link between aging and a major genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia, two related neurodegenerative diseases with shared genetic risk factors. The findings reveal possible new targets for treatment of these and other neurodegenerative diseases.
Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news
AbstractThe deposition of pathologic misfolded proteins in neurodegenerative disorders such as Alzheimer ’s disease, Parkinson’s disease, frontotemporal dementia and amyotrophic lateral sclerosis is hypothesized to burden protein homeostatic (proteostatic) machinery, potentially leading to insufficient capacity to maintain the proteome. This hypothesis has been supported by previous work in our lab oratory, as evidenced by the perturbation of cytosolic protein solubility in response to amyloid plaques in a mouse model of Alzheimer’s amyloidosis. In the current study, we demonstrate changes in proteome sol...
Source: Acta Neuropathologica - Category: Neurology Source Type: research
New analyses shift the view that some forms of amyotrophic lateral sclerosis and frontotemporal dementia are due to defects in a single RNA-binding protein.
Source: eLife - Category: Biomedical Science Tags: Biochemistry and Chemical Biology Human Biology and Medicine Source Type: research
C9orf72-mediated ALS and FTD: multiple pathways to disease, Published online: 17 August 2018; doi:10.1038/s41582-018-0047-2Repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Balendra and Isaacs review the pathological and mechanistic features of C9orf72-associated ALS and FTD, highlighting loss-of-function, gain-of-function and downstream mechanisms.
Source: Nature Reviews Neurology - Category: Neurology Authors: Source Type: research
The analysis of underivatized β-Methylamino-L-alanine (BMAA), BAMA, AEG &2,4-DAB in Pteropus mariannus mariannus specimens using HILIC-LC-MS/MS. Toxicon. 2018 Aug 10;: Authors: Foss AJ, Chernoff N, Aubel MT Abstract β-Methylamino-L-alanine (BMAA) has been identified as the potential cause of the amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) observed in the Chamorro people of Guam. The principal hypothesis for BMAA exposure and intoxication relies on the biomagnification of BMAA in flying fox specimens ingested by the Chamorro people. Although high levels of BMAA w...
Source: Toxicon - Category: Toxicology Authors: Tags: Toxicon Source Type: research
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