title: RNA pathogenesis via Toll-like receptor-activated inflammation in expanded repeat neurodegenerative diseases.
abstract: Previously, we hypothesized that an RNA-based pathogenic pathway has a causal role in the dominantly inherited unstable expanded repeat neurodegenerative diseases. In support of this hypothesis we, and others, have characterized rCAG.rCUG 100 repeat double-strand RNA (dsRNA) as a previously unidentified agent capable of causing pathogenesis in a Drosophila model of neurodegenerative disease. Dicer, Toll, and autophagy pathways have distinct roles in this Drosophila dsRNA pathology. Dicer dependence is accompanied by cleavage of rCAG.rCUG 100 repeat dsRNA down to r(CAG) 7 21-mers. Among the "molecular hallmarks" of this pathway that have been identified in Drosophila, some [i.e., r(CAG) 7 and elevated tumor necrosis factor] correlate with observations in affected people (e.g., Huntington's disease and amyotrophic lateral sclerosis) or in related animal models (i.e., autophagy). The Toll pathway is activated in the presence of repeat-containing dsRNA and toxicity is also dependent on this pathway. How might the endogenously expressed dsRNA mediate Toll-dependent toxicity in neuronal cells? Endogenous RNAs are normally shielded from Toll pathway activation as part of the mechanism to distinguish "self" from "non-self" RNAs. This typically involves post-transcriptional modification of the RNA. Therefore, it is likely that rCAG.rCUG 100 repeat dsRNA has a characteristic property that interferes with or evades this normal mechanism of shielding. We predict that repeat expansion leads to an alteration in RNA structure and/or form that perturbs RNA modification, causing the unshielded repeat RNA (in the form of its Dicer-cleaved products) to be recognized by Toll-like receptors (TLRs), with consequent activation of the Toll pathway leading to loss of cell function and then ultimately cell death. We hypothesize that the proximal cause of expanded repeat neurodegenerative diseases is the TLR recognition (and resultant innate inflammatory response) of repeat RNA as "non-self" due to their paucity of "self" modification.
authors.affiliation: Discipline of Genetics and Centre for Molecular Pathology, School of Molecular and Biomedical Science, The University of Adelaide Adelaide, SA, Australia.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Richards
authors.forename: Saumya E
authors.initials: SE
authors.lastname: Samaraweera
authors.forename: Clare L
authors.initials: CL
authors.lastname: van Eyk
authors.forename: Louise V
authors.initials: LV
authors.lastname: O'Keefe
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Suter
keywords: RNA pathogenesis; Toll-like receptor; expanded repeat diseases; innate inflammation; neuro-degeneration
references.citation: Mediators Inflamm. 2013;2013:342931
references.pmid: 23843682
references.citation: Cell. 2001 Nov 16;107(4):489-99
references.pmid: 11719189
references.citation: Nature. 2008 Jun 19;453(7198):1107-11
references.pmid: 18449188
references.citation: Nature. 2013 Jul 11;499(7457):172-7
references.pmid: 23846655
references.citation: Hum Mol Genet. 2012 Feb 1;21(3):536-47
references.pmid: 22021427
references.citation: Neuron. 2013 Feb 20;77(4):639-46
references.pmid: 23415312
references.citation: Hum Mol Genet. 2005 Apr 15;14(8):1041-8
references.pmid: 15757976
references.citation: Neuron. 2013 May 8;78(3):440-55
references.pmid: 23602499
references.citation: Cell. 2011 Oct 28;147(3):498-508
references.pmid: 22036560
references.citation: Nat Genet. 2012 Dec;44(12):1302-9
references.pmid: 23104007
references.citation: Hum Mol Genet. 2009 Aug 15;18(16):3039-47
references.pmid: 19465745
references.citation: Nat Rev Genet. 2010 Apr;11(4):247-58
references.pmid: 20177426
references.citation: Hum Mol Genet. 2010 Apr 15;19(R1):R77-82
references.pmid: 20368264
references.citation: Neuron. 2011 Oct 20;72(2):257-68
references.pmid: 21944779
references.citation: Trends Biochem Sci. 2013 Apr;38(4):204-9
references.pmid: 23337769
references.citation: Am J Hum Genet. 2004 May;74(5):793-804
references.pmid: 15065017
references.citation: Nature. 1991 Jul 4;352(6330):77-9
references.pmid: 2062380
references.citation: PLoS One. 2012;7(6):e38516
references.pmid: 22715390
references.citation: PLoS Genet. 2011 Mar;7(3):e1001340
references.pmid: 21437269
references.citation: Hum Mol Genet. 2001 Oct 1;10(20):2187-94
references.pmid: 11673400
references.citation: Hum Mol Genet. 2011 Oct 1;20(19):3757-68
references.pmid: 21724553
references.citation: Science. 1993 Oct 22;262(5133):563-6
references.pmid: 7692601
references.citation: Mol Cell. 2002 Jul;10(1):35-44
references.pmid: 12150905
references.citation: J Clin Invest. 2012 Dec;122(12):4461-72
references.pmid: 23160194
references.citation: Cell. 1992 Sep 4;70(5):709-12
references.pmid: 1516128
references.citation: Hum Mol Genet. 2009 Oct 15;18(R2):R130-6
references.pmid: 19808788
references.citation: Cell. 1991 Aug 23;66(4):817-22
references.pmid: 1878973
references.citation: Hum Mol Genet. 2011 Jul 15;20(14):2783-94
references.pmid: 21518731
references.citation: Neurology. 2010 Feb 2;74(5):366-71
references.pmid: 20124201
references.citation: Neurobiol Dis. 2011 Jun;42(3):211-20
references.pmid: 21220013
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):260-5
references.pmid: 21173221
references.citation: Neuron. 2011 Oct 20;72(2):245-56
references.pmid: 21944778
references.citation: Nat Genet. 1993 Jan;3(1):31-5
references.pmid: 8490650
references.citation: Neuron. 2011 Oct 20;72(2):189-90
references.pmid: 22017980
references.citation: Science. 1991 Jun 21;252(5013):1711-4
references.pmid: 1675488
references.citation: J Neurosci. 2011 Nov 9;31(45):16269-78
references.pmid: 22072678
references.citation: Neuroscience. 2011 Apr 14;179:233-43
references.pmid: 21303685
references.citation: PLoS Genet. 2012;8(2):e1002481
references.pmid: 22383888
references.citation: J Cell Biol. 2009 Dec 14;187(6):761-72
references.pmid: 19951898
references.citation: Science. 1991 May 24;252(5009):1179-81
references.pmid: 2031189
references.citation: Nature. 2010 Aug 26;466(7310):1069-75
references.pmid: 20740007
references.citation: Am J Hum Genet. 2011 Jul 15;89(1):121-30
references.pmid: 21683323
references.citation: Cell Stem Cell. 2010 Nov 5;7(5):618-30
references.pmid: 20888316
references.citation: Neurology. 2005 Dec 27;65(12):1958-60
references.pmid: 16380619
references.citation: Am J Med Genet A. 2013 Jul;161A(7):1763-7
references.pmid: 23704040
references.citation: Cell. 2012 Jun 8;149(6):1393-406
references.pmid: 22658674
references.citation: J Exp Med. 2008 Aug 4;205(8):1869-77
references.pmid: 18625748
references.citation: Am J Hum Genet. 2009 Nov;85(5):544-57
references.pmid: 19878914
references.citation: Science. 2013 Mar 15;339(6125):1335-8
references.pmid: 23393093
references.citation: PLoS Genet. 2008 Sep 19;4(9):e1000193
references.pmid: 18802454
references.citation: PLoS Curr. 2011 Apr 13;3:RRN1231
references.pmid: 21826115
references.citation: Cell. 1991 May 31;65(5):905-14
references.pmid: 1710175
references.citation: Hum Mol Genet. 2013 Jul 15;22(14):2811-9
references.pmid: 23525903
references.citation: J Mol Med (Berl). 2013 Jun;91(6):683-91
references.pmid: 23512265