Role of non-coding RNAs in non-aging-related neurological disorders

Vieira, A.S.; Dogini, D.B.; Lopes-Cendes, I.

doi:10.1590/1414-431X20187566

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Brazilian Journal of Medical and Biological Research

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Review • Braz. J. Med. Biol. Res. 51 (8) • 2018 • https://doi.org/10.1590/1414-431X20187566 copy

Role of non-coding RNAs in non-aging-related neurological disorders

Authorship SCIMAGO INSTITUTIONS RANKINGS

Protein coding sequences represent only 2% of the human genome. Recent advances have demonstrated that a significant portion of the genome is actively transcribed as non-coding RNA molecules. These non-coding RNAs are emerging as key players in the regulation of biological processes, and act as "fine-tuners" of gene expression. Neurological disorders are caused by a wide range of genetic mutations, epigenetic and environmental factors, and the exact pathophysiology of many of these conditions is still unknown. It is currently recognized that dysregulations in the expression of non-coding RNAs are present in many neurological disorders and may be relevant in the mechanisms leading to disease. In addition, circulating non-coding RNAs are emerging as potential biomarkers with great potential impact in clinical practice. In this review, we discuss mainly the role of microRNAs and long non-coding RNAs in several neurological disorders, such as epilepsy, Huntington disease, fragile X-associated ataxia, spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), and pain. In addition, we give information about the conditions where microRNAs have demonstrated to be potential biomarkers such as in epilepsy, pain, and ALS.

microRNA; Gene regulation; Molecular biomarkers

Disorder	Gene Affected	Proposed mechanisms associated with Noncoding RNAs	References
FXTAS	FMR1; FMR4	Sequestration of RNA binding protein; antisense transcript	Tassone et al. 2004 ⁵⁸58. Tassone F, Iwahashi C, Hagerman PJ. FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS). RNA Biol 2004; 1: 103–105, doi: 10.4161/rna.1.2.1035. https://doi.org/10.4161/rna.1.2.1035...
DM1	DMPK	Sequestration of RNA binding protein; antisense transcript	Rau et al. 2011 ⁶⁶66. Rau F, Freyermuth F, Fugier C, Villemin J. P, Fischer M. C, Jost, B, et al. Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nature Struct Molec Biol 2011, 18, 840–845, doi: 10.1038/nsmb.2067. https://doi.org/10.1038/nsmb.2067...
SCA1	ATXN1	Altered miRNA pathway	Galka-Marciniak et al. 2012 ⁵⁶56. Galka-Marciniak P, Urbanek MO, Krzyzosiak WJ. Triplet repeats in transcripts: structural insights into RNA toxicity. Biol Chem 2012; 393: 1299–1315, doi: 10.1515/hsz-2012-0218. https://doi.org/10.1515/hsz-2012-0218...
SCA3	ATXN3	An auxiliary toxic long CAG repeat RNA; altered miRNA pathway	Galka-Marciniak et al. 2012 ⁵⁶56. Galka-Marciniak P, Urbanek MO, Krzyzosiak WJ. Triplet repeats in transcripts: structural insights into RNA toxicity. Biol Chem 2012; 393: 1299–1315, doi: 10.1515/hsz-2012-0218. https://doi.org/10.1515/hsz-2012-0218...
SCA7	ATXN7	Antisense transcript repress sense ataxin-7	Tan et al. 2014 ⁶³63. Tan JY, Vance KW, Varela MA, Sirey T, Watson LM, Curtis HJ, et al. Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7. Nat Struct Mol Biol 2014; 21: 955–961, doi: 10.1038/nsmb.2902. https://doi.org/10.1038/nsmb.2902...
SCA8	ATXN8OS; ATXN8	Sequestration of RNA binding protein; antisense transcript	Daughters et al. 2009 ⁶¹61. Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ, et al. RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet 2009; 5: e1000600, doi: 10.1371/journal.pgen.1000600. https://doi.org/10.1371/journal.pgen.100... ; Moseley et al. 2006 ⁶²62. Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, Daughters RS, et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet 2006; 38: 758–769, doi: 10.1038/ng1827. https://doi.org/10.1038/ng1827...
HDL2	JPH3	Antisense transcript; polyQ toxicity	Wojciechowska and Krzyzosiak, 2011 ⁵5. Wojciechowska M, Krzyzosiak WJ. Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum Mol Genet 2011; 20: 3811–3821, doi: 10.1093/hmg/ddr299. https://doi.org/10.1093/hmg/ddr299...
MTLE	P2X7	Down-regulation by miR-22	Jimenez-Mateos et al. 2015 ³3. Jimenez-Mateos EM, Arribas-Blazquez M, Sanz-Rodriguez A, Concannon C, Olivos-Ore LA, Reschke CR, et al. microRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus. Sci Rep 2015; 5: 17486, doi: 10.1038/srep17486. https://doi.org/10.1038/srep17486...
HD	HTT	An auxiliary toxic long CAG repeat RNA; altered miRNA pathway	Wojciechowska and Krzyzosiak, 2011 ⁵5. Wojciechowska M, Krzyzosiak WJ. Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum Mol Genet 2011; 20: 3811–3821, doi: 10.1093/hmg/ddr299. https://doi.org/10.1093/hmg/ddr299...
MTLE	Genes involved with inflammation	Up-regulation of miR-146a expression	Aronica et al. 2010 ³⁷37. Aronica E, Fluiter K, Iyer A, Zurolo E, Vreijling J, van Vliet EA, et al. Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Euro J Neurosci 2010; 31: 1100–1107, doi: 10.1111/j.1460-9568.2010.07122.x. https://doi.org/10.1111/j.1460-9568.2010...
ALS	SOD1 and others	An artificial microRNA may extend survival and delays paralysis; Up regulation of miR-206.	Stoica et al. 2016 ⁷⁹79. Stoica L, Todeasa SH, Toro Cabrera G, Salameh JS, ElMallah MK, Mueller C, et al. Adno associated virus delivered artificial microRNA extends survival and delays paralysis in an amyotrophic lateral sclerosis mouse model. Ann Neurol 2016; 79: 687–700, doi: 10.1002/ana.24618. https://doi.org/10.1002/ana.24618... ; Takahashi et al. 2015 ⁸¹81. Takahashi I, Hama Y, Matsushima M, Hirotani M, Kano T, Hohzen H, et al. Identification of plasma microRNAs as a biomarker of sporadic amyotrophic lateral sclerosis. Mol Brain 2015; 8; 67, doi: 10.1186/s13041-015-0161-7. https://doi.org/10.1186/s13041-015-0161-...
Cortical dysplasia	Lis1	Dysregulation of miR-139-5p	Huang et al. 2014 ⁹⁰90. Huang Y, Jiang J, Zheng G, Chen J, Lu H, Guo H, et al. miR-139-5p modulates cortical neuronal migration by targeting Lis1 in a rat model of focal cortical dysplasia. Int J Mol Med 2014; 33: 1407–1414, doi: 10.3892/ijmm.2014.1703. https://doi.org/10.3892/ijmm.2014.1703...
Pain	Inflammation, neural processing	Dysregulation of miR-1, -16, and -206	Kusuda et al. 2011 ⁸⁶86. Kusuda R, Cadetti F, Ravanelli MI, Sousa TA, Zanon S, De Lucca FL, et al. Differential expression of microRNAs in mouse pain models. Mol Pain 2011; 7: 17, doi: 10.1186/1744-8069-7-17. https://doi.org/10.1186/1744-8069-7-17...

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[1] Correspondence: I. Lopes-Cendes: <icendes@unicamp.br>