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The length of uninterrupted CAG repeats in stem regions of repeat disease associated hairpins determines the amount of short CAG oligonucleotides that are toxic to cells through RNA interference

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Murmann, Andrea E 
Patel, Monal 
Jeong, Si-Yeon 
Bartom, Elizabeth T  ORCID logo
Jennifer Morton, A 


jats:titleAbstract</jats:title>jats:pExtended CAG trinucleotide repeats (TNR) in the genes huntingtin (jats:italicHTT</jats:italic>) and androgen receptor (jats:italicAR</jats:italic>) are the cause of two progressive neurodegenerative disorders: Huntington’s disease (HD) and Spinal and Bulbar Muscular Atrophy (SBMA), respectively. Anyone who inherits the mutant gene in the complete penetrance range (>39 repeats for HD and 44 for SBMA) will develop the disease. An inverse correlation exists between the length of the CAG repeat and the severity and age of onset of the diseases. Growing evidence suggests that it is the length of uninterrupted CAG repeats in the mRNA rather than the length of poly glutamine (polyQ) in mutant (m)jats:italicHTT</jats:italic> protein that determines disease progression. One variant of mjats:italicHTT</jats:italic> (loss of inhibition; LOI) causes a 25 year earlier onset of HD when compared to a reference sequence, despite both coding for a protein that contains an identical number of glutamines. Short 21–22 nt CAG repeat (sCAGs)-containing RNAs can cause disease through RNA interference (RNAi). RNA hairpins (HPs) forming at the CAG TNRs are stabilized by adjacent CCG (in HD) or CUG repeats (in SBMA) making them better substrates for Dicer, the enzyme that processes CAG HPs into sCAGs. We now show that cells deficient in Dicer or unable to mediate RNAi are resistant to the toxicity of the jats:italicHTT</jats:italic> and jats:italicAR</jats:italic> derived HPs. Expression of a small HP that mimics the HD LOI variant is more stable and more toxic than a reference HP. We report that the LOI HP is processed by Dicer, loaded into the RISC more efficiently, and gives rise to a higher quantity of RISC-bound 22 nt sCAGs. Our data support the notion that RNAi contributes to the cell death seen in HD and SBMA and provide an explanation for the dramatically reduced onset of disease in HD patients that carry the LOI variant.</jats:p>



Article, /631/378/1689/364, /631/80/82, /13/89, /13/106, /38, /64, /64/110, /96, article

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Cell Death &amp; Disease

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Springer Science and Business Media LLC