Dataset Information

Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases.

ABSTRACT: For nearly a century, the fruit fly, Drosophila melanogaster, has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, Drosophila has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the Drosophila model to study repeat-expansion associated diseases (READs), such as polyglutamine diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy type 1 (DM1) and type 2 (DM2), and C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia (C9-ALS/FTD). Discoveries regarding the possible mechanisms of RNA toxicity will be focused here. These studies demonstrate Drosophila as an excellent in vivo model system that can reveal novel mechanistic insights into human disorders, providing the foundation for translational research and therapeutic development.

SUBMITTER: Koon AC

PROVIDER: S-EPMC5359753 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases.

Koon Alex C AC Chan Ho Yin Edwin HY

Frontiers in cellular neuroscience 20170321

For nearly a century, the fruit fly, Drosophila melanogaster, has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, Drosophila has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the Drosophila model to study repeat-expansion associated dis ...[more]

PMID: 28377694

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Project description:Dominantly inherited expanded repeat neurodegenerative diseases are typically caused by the expansion of existing variable copy number tandem repeat sequences in otherwise unrelated genes. Repeats located in translated regions encode polyglutamine that is thought to be the toxic agent, however in several instances the expanded repeat is in an untranslated region, necessitating multiple pathogenic pathways or an alternative common toxic agent. As numerous clinical features are shared by several of these diseases, and expanded repeat RNA is a common intermediary, RNA has been proposed as a common pathogenic agent. Various forms of repeat RNA are toxic in animal models, by multiple distinct pathways. In Drosophila, repeat-containing double-stranded RNA (rCAG.rCUG~100) toxicity is dependent on Dicer processing evident with the presence of single-stranded rCAG7, which have been detected in affected HD brains. Microarray analysis of Drosophila rCAG.rCUG~100 repeat RNA toxicity revealed perturbation of several pathways including innate immunity. Recent reports of elevated circulating cytokines prior to clinical onset, and age-dependent increased inflammatory signaling and microglia activation in the brain, suggest that immune activation precedes neuronal toxicity. Since the Toll pathway is activated by certain forms of RNA, we assessed the role of this pathway in RNA toxicity. We find that rCAG.rCUG~100 activates Toll signaling and that RNA toxicity is dependent on this pathway. The sensitivity of RNA toxicity to autophagy further implicates innate immune activation. Expression of rCAG.rCUG~100 was therefore directed in glial cells and found to be sufficient to cause neuronal dysfunction. Non-autonomous toxicity due to expanded repeat-containing double-stranded RNA mediated activation of innate immunity is therefore proposed as a candidate pathway for this group of human genetic diseases. The heads from newly eclosed male Drosophila were used for RNA extraction and profiling on Affymetrix Drosophile Genome 2.0 microarrays. Nine samples were analysed, representing control and experimental lines. Two independent lines of rCAG.rCUG~100 double-stranded RNA were analysed in triplicate. These were compared to 4xUAS control analysed in triplicate. All transgenes were expressed using the elavII-GAL4 pan-neuronal driver. Candidates were selected from the pool of transcripts which showed a 'present' call in all samples. T-tests were performed on raw values to determine samples that showed a significant difference with a P-value < 0.05.

Project description:Previously, we hypothesized that an RNA-based pathogenic pathway has a causal role in the dominantly inherited unstable expanded repeat neurodegenerative diseases. In support of this hypothesis we, and others, have characterized rCAG.rCUG 100 repeat double-strand RNA (dsRNA) as a previously unidentified agent capable of causing pathogenesis in a Drosophila model of neurodegenerative disease. Dicer, Toll, and autophagy pathways have distinct roles in this Drosophila dsRNA pathology. Dicer dependence is accompanied by cleavage of rCAG.rCUG 100 repeat dsRNA down to r(CAG) 7 21-mers. Among the "molecular hallmarks" of this pathway that have been identified in Drosophila, some [i.e., r(CAG) 7 and elevated tumor necrosis factor] correlate with observations in affected people (e.g., Huntington's disease and amyotrophic lateral sclerosis) or in related animal models (i.e., autophagy). The Toll pathway is activated in the presence of repeat-containing dsRNA and toxicity is also dependent on this pathway. How might the endogenously expressed dsRNA mediate Toll-dependent toxicity in neuronal cells? Endogenous RNAs are normally shielded from Toll pathway activation as part of the mechanism to distinguish "self" from "non-self" RNAs. This typically involves post-transcriptional modification of the RNA. Therefore, it is likely that rCAG.rCUG 100 repeat dsRNA has a characteristic property that interferes with or evades this normal mechanism of shielding. We predict that repeat expansion leads to an alteration in RNA structure and/or form that perturbs RNA modification, causing the unshielded repeat RNA (in the form of its Dicer-cleaved products) to be recognized by Toll-like receptors (TLRs), with consequent activation of the Toll pathway leading to loss of cell function and then ultimately cell death. We hypothesize that the proximal cause of expanded repeat neurodegenerative diseases is the TLR recognition (and resultant innate inflammatory response) of repeat RNA as "non-self" due to their paucity of "self" modification.

Dataset Information

Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases.

Publications

<i>Drosophila melanogaster</i> As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases.

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