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Role in Neurological Disorders

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G-quadruplexes have been implicated in neurological disorders through two main mechanisms. The first is through expansions of G-repeats within genes that lead to the formation of G-quadruplex structures that directly cause disease, as is the case with the C9orf72 gene and amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). The second mechanism is through mutations that affect the expression of G-quadruplex binding proteins, as seen in the FMR1 gene and Fragile X Syndrome. [1]

The C9orf72 gene codes for the protein C9orf72 which is found throughout the brain in neuronal cytoplasm and at presynaptic terminals.[2] Mutations of the C9orf72 gene have been linked to the development of FTD and ALS.[3] These two diseases have a causal relationship to GGGGCC (G4C2) repeats within the 1st intron of C9orf72 gene. Normal individuals typically have around 2 to 8 G4C2 repeats, but individuals with FTD or ALS have from 500 to several thousand G4C2 repeats.[4][5] The transcribed RNA of these repeats have been shown to form stable G-quadruplexes, with evidence showing that the G4C2 repeats in DNA have the ability to form mixed parallel-antiparallel G-quadruplex structures as well.[6][7] These RNA transcripts containing G4C2 repeats were shown to bind and separate a wide variety of proteins, including nucleolin. Nucleolin is involved in the synthesis and maturation of ribosomes within the nucleus, and separation of nucleolin by the mutated RNA transcripts impairs nucleolar function and ribosomal RNA synthesis.[8]

Fragile X mental retardation protein (FMRP) is a widely expressed protein coded by the fragile X mental retardation gene 1 (FMR1) that binds to G-quadruplex secondary structures in neurons and is involved in synaptic plasticity.[9] FMRP acts as a negative regulator of translation, and its binding stabilizes G-quadruplex structures in mRNA transcripts, inhibiting ribosome elongation of mRNA in the neuron's dendrite and controlling the timing of the transcript's expression.[10][11] Mutations of this gene can cause the development of Fragile X Syndrome, autism, and other neurological disorders.[12] Specifically, Fragile X Syndrome is caused by an increase from 50 to over 200 CGG repeats within exon 13 of the FMR1 gene. This repeat expansion promotes DNA methylation and other epigenetic heterochromatin modifications of FMR1 that prevent the transcription of the gene, leading to pathological low levels of FMRP.[13][14]

References

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  1. ^ Roberto Simone, Pietro Fratta, Stephen Neidle, Gary N. Parkinson, Adrian M. Isaacs (May 2015). "G-quadruplexes: Emerging roles in neurodegenerative diseases and the non-coding transcriptome". Federation of European Biochemical Societies. 589 (14): 1653–1668. doi:10.1016/j.febslet.2015.05.003.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ C9orf72 chromosome 9 open reading frame 72 [Homo sapiens] - Gene - NCBI
  3. ^ Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002). "The prevalence of frontotemporal dementia". Neurology. 58 (11): 1615–21. doi:10.1212/WNL.58.11.1615. PMID 12058088.
  4. ^ Rutherford NJ, Heckman MG, Dejesus-Hernandez M, Baker MC, Soto-Ortolaza AI, Rayaprolu S, Stewart H, Finger E, Volkening K, Seeley WW, Hatanpaa KJ, Lomen-Hoerth C, Kertesz A, Bigio EH, Lippa C, Knopman DS, Kretzschmar HA, Neumann M, Caselli RJ, White CL 3rd, Mackenzie IR, Petersen RC, Strong MJ, Miller BL, Boeve BF, Uitti RJ, Boylan KB, Wszolek ZK, Graff-Radford NR, Dickson DW, Ross OA, Rademakers R. (Dec 2012). "Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype". Neurobiology of Aging. 33 (12): 2950.e5-7. doi:10.1016/j.neurobiolaging.2012.07.005. PMID 22840558.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  5. ^ Jon Beck, Mark Poulter, Davina Hensman, Jonathan D. Rohrer, Colin J. Mahoney, Gary Adamson, Tracy Campbell, James Uphill, Aaron Borg, Pietro Fratta, Richard W. Orrell, Andrea Malaspina, James Rowe, Jeremy Brown, John Hodges, Katie Sidle, James M. Polke, Henry Houlden, Jonathan M. Schott, Nick C. Fox, Martin N. Rossor, Sarah J. Tabrizi, Adrian M. Isaacs, John Hardy, Jason D. Warren, John Collinge, and Simon Mead (March 2013). "Large C9orf72 Hexanucleotide Repeat Expansions Are Seen in Multiple Neurodegenerative Syndromes and Are More Frequent Than Expected in the UK Population". The American Journal of Human Genetics. 92 (3): 345–353. doi:10.1016/j.ajhg.2013.01.011.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Pietro Fratta, Sarah Mizielinska, Andrew J. Nicoll, Mire Zloh, Elizabeth M. C. Fisher, Gary Parkinson, and Adrian M. Isaacs (December 2012). "C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes". Scientific Reports. 2: 1016.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Kaalak Reddy, Bita Zamiri, Sabrina Y. R. Stanley, Robert B. Macgregor Jr. and Christopher E. Pearson (April 2013). "The Disease-associated r(GGGGCC)n Repeat from the C9orf72 Gene Forms Tract Length-dependent Uni- and Multimolecular RNA G-quadruplex Structures". Journal of Biological Chemistry. 288 (14): 9860–9866. doi:10.1074/jbc.C113.452532.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  8. ^ Aaron R. Haeusler, Christopher J. Donnelly, Goran Periz, Eric A. J. Simko, Patrick G. Shaw, Min-Sik Kim, Nicholas J. Maragakis, Juan C. Troncoso, Akhilesh Pandey, Rita Sattler, Jeffrey D. Rothstein & Jiou Wang (March 2014). "C9orf72 nucleotide repeat structures initiate molecular cascades of disease". Nature. 507: 195–200. doi:10.1038/nature13124.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Darnell, J. C., Jensen, K. B., Jin, P., Brown, V., Warren, S. T., Darnell. R. B. (November 2001). "Fragile X Mental Retardation Protein Targets G Quartet mRNAs Important for Neuronal Function". Cell. 107 (4): 489–499. doi:10.1016/S0092-8674(01)00566-9.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Ceman, S., O'Donnell, W. T., Reed, M., Patton, S., Pohl, J., Warren, S. T. (December 2003). "Phosphorylation influences the translation state of FMRP-associated polyribosomes". Human Molecular Genetics. 12 (24): 3295–3305. doi:10.1093/hmg/ddg350.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Fahling, M., Mrowka, R., Steege, A., Kirschner, K. M., Benko, E., Forstera, B., Persson, P. B., Thiele, B. J., Meier, J. C., Scholz, H. (Dec 2008). "Translational Regulation of the Human Achaete-scute Homologue-1 by Fragile X Mental Retardation Protein". Journal of Biological Chemistry. 284: 4255–4266. doi:10.1074/jbc.M807354200.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  12. ^ "Fragile X Mental Retardation" The Human Gene Compendium
  13. ^ Pieretti, M., Zhang, F., Fu, Y., Warren, S. T., Oostra, B. A., Caskey, C. T., Nelson, D. L. (August 1991). "Absence of expression of the FMR-1 gene in fragile X syndrome". Cell. 66 (4): 816–822. doi:10.1016/0092-8674(91)90125-I.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Sutcliffe, J. S., Nelson, D. L., Zhang, F., Pieretti, M., Caskey, C. T., Saxe, D., Warren, S. T. (September 1992). "DNA methylation represses FMR-1 transcription in fragile X syndrome". Human Molecular Genetics. 1 (6): 397–400. doi:10.1093/hmg/1.6.397.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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