Blocking a Long Noncoding RNA Reduces Stroke Damage in Rat Model

Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. This somewhat arbitrary limit distinguishes lncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. LncRNAs have been found to be involved in numerous biological roles including imprinting, epigenetic gene regulation, cell cycle and apoptosis, and metastasis and prognosis in solid tumors. Most lncRNAs are expressed only in a few cells rather than whole tissues, or they are expressed at very low levels, making them difficult to study.

In addition to protein-coding RNAs, many classes of noncoding RNAs, including lncRNAs, undergo changes in the brain following a stroke. To better understand the roll of non-coding RNAs in stroke, investigators at the University of Wisconsin-Madison (USA) evaluated the functional significance of an lncRNA called FosDT (Fos downstream transcript) that is coded on the same chromosome as the FOS gene (FBJ murine osteosarcoma viral oncogene homolog). The FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. In some cases, expression of the FOS gene has also been associated with apoptotic cell death.

In the current study, ischemic stroke was induced in laboratory rats by blocking an artery in the brain for one hour. Some of the animals were treated with anti-sense RNA that blocked the production of the lncRNA FosDT.

Results published in the December 16, 2015, issue of the Journal of Neuroscience revealed that stroke induced production of FOS and FosDT in the untreated animals. In the treated animals FosDT knockdown significantly ameliorated post-ischemic motor deficits and reduced the infarct volume. These effects of FosDT in part were due to its interactions with chromatin-modifying proteins Sin3a and coREST (corepressors of the transcription factor REST) and subsequent derepression of REST-downstream genes GRIA2, NFkappaB2, and GRIN1.

"Stroke influences the expression of all types of RNA, and this RNA has a broad influence throughout the cell after the blood supply is restored, in what we call reperfusion injury," said senior author Dr. Raghu Vemuganti, professor of neurological surgery at the University of Wisconsin-Madison. "A few years ago, our lab started to look at how stroke affects noncoding RNA. Two years ago, we identified about 200 types of various lncRNAs that greatly increase or decrease after stroke, and zeroed in on one that we named FosDT. We knew that the level of FosDT went up more than tenfold in the rat brain within three hours after the stroke. We thought, if we block FosDT after the stroke, would it make any difference in the amount of structural damage or behavioral disability?"

"We did not change the initial insult, caused by lack of oxygen," said Dr. Vemuganti, "but this targeted approach greatly reduced the damage after one week. We cannot completely reverse the post-stroke damage, but the total damage decreased by one-third. If we can protect this much brain tissue from stroke, that would be an enormous improvement."

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University of Wisconsin-Madison