Long non-coding RNAs in Huntington's disease neurodegeneration

Rory Johnson
Neurobiology of Disease 2012, 46 (2): 245-54
Neurodegeneration in the brains of Huntington's disease patients is accompanied by widespread changes in gene regulatory networks. Recent studies have found that these changes are not restricted to protein-coding genes, but also include non-coding RNAs (ncRNAs). One particularly abundant but poorly understood class of ncRNAs is the long non-coding RNAs (lncRNAs), of which at least ten thousand have been identified in the human genome. Although we presently know little about their function, lncRNAs are widely expressed in the mammalian nervous system, and many are likely to play critical roles in neuronal development and activity. LncRNAs are now being implicated in neurodegenerative processes, including Alzheimer's (AD) and Huntington's disease (HD). In the present study, I discuss the potential significance of lncRNAs in HD. To support this, I have mined existing microarray data to discover seven new lncRNAs that are dysregulated in HD brains. Interestingly, several of these contain genomic binding sites for the transcriptional repressor REST, a key mediator of transcriptional changes in HD, including the known REST target lncRNA, DGCR5. Previously described lncRNAs TUG1 (necessary for retinal development) and NEAT1 (a structural component of nuclear paraspeckles) are upregulated in HD caudate, while the brain-specific tumour-suppressor MEG3 is downregulated. Three other lncRNAs of unknown function are also significantly changed in HD brains. Many lncRNAs regulate gene expression through formation of epigenetic ribonucleoprotein complexes, including TUG1 and MEG3. These findings lead me to propose that lncRNA expression changes in HD are widespread, that many of these result in altered epigenetic gene regulation in diseased neurons, and that contributes to neurodegeneration. Therefore, elucidating lncRNA network changes in HD may be important in understanding and treating this and other neurodegenerative processes.

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