Small RNAs in Neurological Disorders

Li Lin, Emory University School of Medicine, Atlanta, Georgia, USA
Angela V Vitale, Emory University School of Medicine, Atlanta, Georgia, USA
Peng Jin, Emory University School of Medicine, Atlanta, Georgia, USA

Published online: April 2010

DOI: 10.1002/9780470015902.a0022385

Small RNAs (ribonucleic acids) are a group of noncoding RNA molecules with modulation functions that span a broad range, from RNA modification to protein synthesis regulation. The expression of small RNAs is found to be widespread in all eukaryotes, and more than a third of protein-coding genes in the human genome are regulated by small RNAs. Mounting evidence suggests that the appropriate spatiotemporal expression of small RNAs, in particular microRNAs (miRNAs), is required for both brain morphogenesis and nervous system development. Moreover, dysregulation of specific miRNAs is possibly correlated with the pathogenesis of neurodevelopmental disorders. Understanding the potential roles of small regulatory RNAs in neural development and various human neurological disorders could reveal therapeutic applications that involve restoring or inhibiting the function of small RNAs.

Key Concepts:

  • Small RNAs have been found in all major groups of eukaryotes.
  • Small RNAs are divided into four classes: microRNAs, small interacting RNAs, Piwi-interacting RNAs and small nucleolar RNAs.
  • In humans, microRNAs play important functional roles, interacting with at least 30% of all mRNAs.
  • MicroRNAs are highly involved not only in normal brain function, but also in many developmental disorders.
  • Known to act on mRNAs, microRNAs will degrade, translationally inhibit or even upregulate mRNA expression.
  • One microRNA can affect the course of several neurodevelopmental disorders.
  • A full understanding of microRNA function will yield possible medicinal treatments.

Keywords: microRNAs; Alzheimer disease; Parkinson disease; Huntington disease; fragile X syndrome; Rett syndrome; DiGeorge syndrome; Down syndrome; multiple sclerosis; spina bifida

Figure 1. miRNA and siRNA biogenesis. miRNAs are initially transcribed from genomic DNA to long primary transcripts (pri-miRNAs) that are capped and polyadenylated. The pri-miRNAs are then processed by a Drosha/DGCR8 complex to yield stem–loop structures that are precursors of miRNAs (pre-miRNAs). After pre-miRNAs are transported to cytoplasm by Exportin5/RnaGTP, they undergo further processing by Dicer. One strand of the miRNA duplex is selectively loaded into the RNA-induced silencing complex (RISC) and guides target transcripts by mRNA cleavage or translation repression. dsRNAs (dsRNAs) are cleaved via Dicer. These small RNAs are incorporated into the RISC, and the guide strand of the siRNA recognises target sites to direct mRNA cleavage.
Figure 2. Ping-pong model of piRNA production. Antisense primary piRNAs are generated from transposons and interact with Piwi/Aub. Piwi/Aub-antisense piRNA complex binds to sense transcripts and directs their cleavage. Subsequently, the Piwi-class Argonaute protein (Ago3) binds the resulting sense piRNA and directs the cleavage of target antisense transcripts, producing new antisense piRNAs.
Figure 3. snoRNA assembly and transport. snoRNAs are synthesised within pre-mRNA introns by exonucleolytic trimming. A single snoRNA molecule is then folded and assembled by four snoRNA core proteins to form snoRNA.
close
 References
    Amir RE, Van den Veyver IB, Wan M et al. (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics 23: 185–188.
    Ang SL (2006) Transcriptional control of midbrain dopaminergic neuron development. Development 133: 3499–3506.
    Armstrong DD (1997) Review of Rett syndrome. Journal of Neuropathology and Experimental Neurology 56: 843–849.
    Berezikov E, Guryev V, van de Belt J et al. (2005) Phylogenetic shadowing and computational identification of human microRNA genes. Cell 120: 21–24.
    Boissonneault V, Plante I, Rivest S et al. (2009) MicroRNA-298 and microRNA-328 regulate expression of mouse beta-amyloid precursor protein-converting enzyme 1. Journal of Biological Chemistry 284: 1971–1981.
    Carrettiero DC, Hernandez I, Neveu P et al. (2009) The cochaperone BAG2 sweeps paired helical filament-insoluble tau from the microtubule. Journal of Neuroscience 29: 2151–2161.
    Du C, Liu C, Kang J et al. (2009) MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nature Immunology 10: 1252–1259.
    Du T and Zamore PD (2005) microPrimer: the biogenesis and function of microRNA. Development 132: 4645–4652.
    Ehninger D, Li W, Fox K et al. (2008) Reversing neurodevelopmental disorders in adults. Neuron 60: 950–960.
    Filipowicz W, Bhattacharyya SN and Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature Reviews. Genetics 9: 102–114.
    Filipowicz W and Pogacic V (2002) Biogenesis of small nucleolar ribonucleoproteins. Current Opinion in Cell Biology 14: 319–327.
    Freeman JW, Simmons M and Matos E (2007) Parkinson disease: an incremental challenge. South Dakota Medine 60: 481, 483–484.
    Fuchs J, Mueller JC, Lichtner P et al. (2009) The transcription factor PITX3 is associated with sporadic Parkinson's disease. Neurobiology of Aging 30: 731–738.
    Girard A, Sachidanandam R, Hannon GJ et al. (2006) A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 442: 199–202.
    Gunawardane LS, Saito K, Nishida KM et al. (2007) A slicer-mediated mechanism for repeat-associated siRNA 5¢ end formation in Drosophila. Science 315: 1587–1590.
    Gunzburg MJ, Perugini MA and Howlett GJ (2007) Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E. Journal of Biological Chemistry 282: 35831–35841.
    Hamilton AJ and Baulcombe DC (1999) A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 286: 950–952.
    Han J, Lee Y, Yeom KH et al. (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes & Development 18: 3016–3027.
    Hebert SS and De Strooper B (2009) Alterations of the microRNA network cause neurodegenerative disease. Trends in Neurosciences 32: 199–206.
    Hebert SS, Horre K, Nicolai L et al. (2008) Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proceedings of the National Academy of Sciences of the USA 105: 6415–6420.
    Huang W and Li MD (2009) Nicotine modulates expression of miR-140*, which targets the 3¢-untranslated region of dynamin 1 gene (Dnm1). International Journal of Neuropsychopharmacology 12: 537–546.
    Jin P, Alisch RS and Warren ST (2004a) RNA and microRNAs in fragile X mental retardation. Nature Cell Biology 6: 1048–1053.
    Jin P, Zarnescu DC, Ceman S et al. (2004b) Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nature Neuroscience 7: 113–117.
    Johnson R, Zuccato C, Belyaev ND et al. (2008) A microRNA-based gene dysregulation pathway in Huntington's disease. Neurobiology of Disease 29: 438–445.
    Kim J, Inoue K, Ishii J et al. (2007) A microRNA feedback circuit in midbrain dopamine neurons. Science 317: 1220–1224.
    Klattenhoff C and Theurkauf W (2008) Biogenesis and germline functions of piRNAs. Development 135: 3–9.
    Kuhn DE, Nuovo GJ, Terry AV Jr. et al. (2009) Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains. Journal of Biological Chemistry 285: 1529–1543.
    Lee RC, Feinbaum RL and Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75: 843–854.
    Lin H (2007) piRNAs in the germ line. Science 316: 397.
    Lugli G, Larson J, Martone ME et al. (2005) Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain-dependent manner. Journal of Neurochemistry 94: 896–905.
    Lukiw WJ (2007) Micro-RNA speciation in fetal, adult and Alzheimer's disease hippocampus. Neuroreport 18: 297–300.
    Lukiw WJ, Zhao Y and Cui JG (2008) An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. Journal of Biological Chemistry 283: 31315–31322.
    van den Munckhof P, Luk KC, Ste-Marie L et al. (2003) Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development 130: 2535–2542.
    Nakamura K and Aminoff MJ (2007) Huntington's disease: clinical characteristics, pathogenesis and therapies. Drugs of Today (Barcelona) 43: 97–116.
    Nomura T, Kimura M, Horii T et al. (2008) MeCP2-dependent repression of an imprinted miR-184 released by depolarization. Human Molecular Genetics 17: 1192–1199.
    Ohyagi Y and Tabira T (2006) Intracellular amyloid beta-protein and its associated molecules in the pathogenesis of Alzheimer's disease. Mini Reviews in Medical Chemistry 6: 1075–1080.
    Okamura K and Lai EC (2008) Endogenous small interfering RNAs in animals. Nature Reviews. Molecular Cell Biology 9: 673–678.
    Reichow SL, Hamma T, Ferre-D'Amare AR et al. (2007) The structure and function of small nucleolar ribonucleoproteins. Nucleic Acids Research 35: 1452–1464.
    Rekate HL (2009) The pediatric neurosurgical patient: the challenge of growing up. Seminars in Pediatric Neurology 16: 2–8.
    Ruby JG, Jan CH and Bartel DP (2007) Intronic microRNA precursors that bypass Drosha processing. Nature 448: 83–86.
    Stamey W and Jankovic J (2008) Impulse control disorders and pathological gambling in patients with Parkinson disease. Neurologist 14: 89–99.
    Sullivan KE (2004) The clinical, immunological, and molecular spectrum of chromosome 22q11.2 deletion syndrome and DiGeorge syndrome. Current Opinion in Allergy and Clinical Immunology 4: 505–512.
    Turner RS (2006) Alzheimer's disease. Seminars in Neurology 26: 499–506.
    Vasudevan S, Tong Y and Steitz JA (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318: 1931–1934.
    Vo N, Klein ME, Varlamova O et al. (2005) A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proceedings of the National Academy of Sciences of the USA 102: 16426–16431.
    Wang G, van der Walt JM, Mayhew G et al. (2008) Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. American Journal of Human Genetics 82: 283–289.
    Warren ST and Nelson DL (1994) Advances in molecular analysis of fragile X syndrome. JAMA 271: 536–542.
    Xu XL, Li Y, Wang F et al. (2008) The steady-state level of the nervous-system-specific microRNA-124a is regulated by dFMR1 in Drosophila. Journal of Neuroscience 28: 11883–11889.
    Yang Y, Xu S, Xia L et al. (2009) The bantam microRNA is associated with drosophila fragile X mental retardation protein and regulates the fate of germline stem cells. PLoS Genetics 5: e1000444.
    Yoo AS, Staahl BT, Chen L et al. (2009) MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460: 642–646.
    Zhao JJ, Sun DG, Wang J et al. (2008) Retinoic acid downregulates microRNAs to induce abnormal development of spinal cord in spina bifida rat model. Childs Nervous System 24: 485–492.
    Zito K, Scheuss V, Knott G et al. (2009) Rapid functional maturation of nascent dendritic spines. Neuron 61: 247–258.
 Further Reading
    Kocerha J, Kauppinen S and Wahlestedt C (2009) microRNAs in CNS disorders. Neuromolecular Medicine 11: 162–172.
    Mattick JS and Makunin IV (2006) Non-coding RNA. Human Molecular Genetics 15(1): R17–R29.
    Presutti C, Rosati J, Vincenti S et al. (2006) Non coding RNA and brain. BMC Neuroscience 7(suppl. 1): S5.
    Rogaev EI (2005) Small RNAs in human brain development and disorders. Biochemistry 70: 1404–1407.
    Sun BK and Tsao H (2008) Small RNAs in development and disease. Journal of the American Academy of Dermatology 59: 725–737 quiz 738–740.
    Zhou R, Yuan P, Wang Y et al. (2009) Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers. Neuropsychopharmacology 34: 1395–1405.

Related Sub-Topics:

Neurobiology of Disease | Organisation of the Nervous System | Nervous System Development | Molecular Genetics of Common and Complex Disease | Genetics of Intelligence and Cognition | Gene Expression Profiling of Genetic Disease | Transcriptional Regulation | RNA Structure and Function | Noncoding RNA
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Small RNAs in Neurological Disorders
 
How to Cite close
Lin, Li, Vitale, Angela V, and Jin, Peng(Apr 2010) Small RNAs in Neurological Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022385]