Potential Transfer of Polyglutamine and CAG-Repeat RNA in Extracellular Vesicles in Huntington's Disease: Background and Evaluation in Cell Culture
| Autor: | Erik R. Abels, Julia Margulis, Steve Finkbeiner, Xuan Zhang, Jasmina S. Redzic, Xandra O. Breakefield |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Huntington's Disease Neurodegenerative Exosomes Exon Mice 2.1 Biological and endogenous factors Aetiology Cells Cultured Genetics Huntingtin Protein Cultured Neurodegeneration General Medicine Pharmacology and Pharmaceutical Sciences Cell biology Huntington Disease Neurological Huntington’s disease Biotechnology Cells Green Fluorescent Proteins Biology Real-Time Polymerase Chain Reaction Article 03 medical and health sciences Cellular and Molecular Neuroscience Extracellular Vesicles Rare Diseases Huntington's disease Trinucleotide repeat medicine Animals Humans Messenger RNA Neurology & Neurosurgery HEK 293 cells Neurosciences RNA Cell Biology medicine.disease Brain Disorders Neostriatum 030104 developmental biology Orphan Drug Cell culture Biochemistry and Cell Biology Trinucleotide repeat expansion Peptides Trinucleotide Repeat Expansion |
| Zdroj: | Cellular and molecular neurobiology, vol 36, iss 3 |
| Popis: | In Huntington's disease (HD) the imperfect expanded CAG repeat in the first exon of the HTT gene leads to the generation of a polyglutamine (polyQ) protein, which has some neuronal toxicity, potentially mollified by formation of aggregates. Accumulated research, reviewed here, implicates both the polyQ protein and the expanded repeat RNA in causing toxicity leading to neurodegeneration in HD. Different theories have emerged as to how the neurodegeneration spreads throughout the brain, with one possibility being the transport of toxic protein and RNA in extracellular vesicles (EVs). Most cell types in the brain release EVs and these have been shown to contain neurodegenerative proteins in the case of prion protein and amyloid-beta peptide. In this study, we used a model culture system with an overexpression of HTT-exon 1 polyQ-GFP constructs in human 293T cells and found that the EVs did incorporate both the polyQ-GFP protein and expanded repeat RNA. Striatal mouse neural cells were able to take up these EVs with a consequent increase in the green fluorescent protein (GFP) and polyQ-GFP RNAs, but with no evidence of uptake of polyQ-GFP protein or any apparent toxicity, at least over a relatively short period of exposure. A differentiated striatal cell line expressing endogenous levels of Hdh mRNA containing the expanded repeat incorporated more of this mRNA into EVs as compared to similar cells expressing this mRNA with a normal repeat length. These findings support the potential of EVs to deliver toxic expanded trinucleotide repeat RNAs from one cell to another, but further work will be needed to evaluate potential EV and cell-type specificity of transfer and effects of long-term exposure. It seems likely that expanded HD-associated repeat RNA may appear in biofluids and may have use as biomarkers of disease state and response to therapy. |
| Databáze: | OpenAIRE |
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