Initiation and regulatory mechanism of C9ORF72 (G4C2)n RAN translation

doi:10.3969/j.issn.1674-8115.2022.10.015

Abstract

Abstract:

As one of the main pathogenic mechanisms of the microsatellite repeat expansion diseases, the repeats from the abnormal DNA expansion produce toxic proteins through repeat-associated non-AUG (RAN) translation, which can causes neuronal death. Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons, while frontotemporal dementia (FTD) is a less common early-onset dementia compared to Alzheimer′s disease. C9ORF72 (G₄C₂)_n abnormal expansion is the most common cause of ALS/FTD. Three mechanisms have been proposed for abnormal expansion of (G₄C₂)_n in C9ORF72: ① The C9ORF72 loss-of-function results from the transcription suppression of C9ORF72 caused by the abnormal expansion of (G₄C₂)_n in C9ORF72. ② The RNA foci from the abnormal expansion of (G₄C₂)_n in C9ORF72, which bind to multiple RNA binding protein (RBP), lead to the dysfunction of these RBP. ③ The repeats from the abnormal expansion of (G₄C₂)_n in C9ORF72 undergoing RAN translation produce the dipeptide repeat proteins (DPRs), which results in their toxic gain-of-function. Many studies have evidenced that RAN translation plays a pivotal role in disease progression. While a lot of studies focus on the pathologic mechanism of DPRs, the initiation and regulation mechanism of C9ORF72 (G₄C₂)_n RAN translation is unknown and severely hinders the application of RAN translation as the therapeutic target in ALS/FTD. This review summarizes the most updated literatures on initiation and regulation mechanism of C9ORF72 (G₄C₂)_n RAN translation and discusses the feasibility of reducing cellular toxicity and increasing neuron survival by targeting C9ORF72 (G₄C₂)_n RAN translation.

Key words: C9ORF72 mutation, abnormal expansion of GGGGCC repeat, repeat associated non-AUG (RAN) translation, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD)

CLC Number:

FENG Yiyuan, XU Zhongyun, DING Lin, YIN Yafu, WANG Hui, CHENG Weiwei. Initiation and regulatory mechanism of C9ORF72 (G₄C₂)_n RAN translation[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(10): 1482-1489.

Figures/Tables 2

TrendMD

References 63

1	NELSON D L, ORR H T, WARREN S T. The unstable repeats: three evolving faces of neurological disease[J]. Neuron, 2013, 77(5): 825-843.
2	CASTELLI L M, HUANG W P, LIN Y H, et al. Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders[J]. Biochem Soc Trans, 2021, 49(2): 775-792.
3	MACDONALD M E, AMBROSE C M, DUYAO M P, et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group[J]. Cell, 1993, 72(6): 971-983.
4	VERKERK A J, PIERETTI M, SUTCLIFFE J S, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome[J]. Cell, 1991, 65(5): 905-914.
5	BROOK J D, MCCURRACH M E, HARLEY H G, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member[J]. Cell, 1992, 69(2): 385.
6	FU Y H, PIZZUTI A, FENWICK R G Jr, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy[J]. Science, 1992, 255(5049): 1256-1258.
7	DEJESUS-HERNANDEZ M, MACKENZIE I R, BOEVE B F, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS[J]. Neuron, 2011, 72(2): 245-256.
8	BANEZ-CORONEL M, RANUM L P W. Repeat-associated non-AUG (RAN) translation: insights from pathology[J]. Lab Invest, 2019, 99(7): 929-942.
9	ZU T, GIBBENS B, DOTY N S, et al. Non-ATG-initiated translation directed by microsatellite expansions[J]. Proc Natl Acad Sci USA, 2011, 108(1): 260-265.
10	TODD P K, OH S Y, KRANS A, et al. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome[J]. Neuron, 2013, 78(3): 440-455.
11	SELLIER C, BUIJSEN R A M, HE F, et al. Translation of expanded CGG repeats into FMRpolyG is pathogenic and may contribute to fragile X tremor ataxia syndrome[J]. Neuron, 2017, 93(2): 331-347.
12	MORI K, WENG S M, ARZBERGER T, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS[J]. Science, 2013, 339(6125): 1335-1338.
13	GENDRON T F, BIENIEK K F, ZHANG Y J, et al. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS[J]. Acta Neuropathol, 2013, 126(6): 829-844.
14	ASH P E, BIENIEK K F, GENDRON T F, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS[J]. Neuron, 2013, 77(4): 639-646.
15	BAÑEZ-CORONEL M, AYHAN F, TARABOCHIA A D, et al. RAN translation in Huntington disease[J]. Neuron, 2015, 88(4): 667-677.
16	RENTON A E, MAJOUNIE E, WAITE A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD[J]. Neuron, 2011, 72(2): 257-268.
17	SMITH B N, NEWHOUSE S, SHATUNOV A, et al. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder[J]. Eur J Hum Genet, 2013, 21(1): 102-108.
18	MAJOUNIE E, RENTON A E, MOK K, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study[J]. Lancet Neurol, 2012, 11(4): 323-330.
19	MACKENZIE I R, ARZBERGER T, KREMMER E, et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations[J]. Acta Neuropathol, 2013, 126(6): 859-879.
20	ZU T, LIU Y J, BAÑEZ-CORONEL M, et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia[J]. Proc Natl Acad Sci USA, 2013, 110(51): E4968-E4977.
21	LOPEZ-GONZALEZ R, LU Y B, GENDRON T F, et al. Poly(GR) in C9ORF72-related ALS/FTD compromises mitochondrial function and increases oxidative stress and DNA damage in iPSC-derived motor neurons[J]. Neuron, 2016, 92(2): 383-391.
22	ZHANG Y J, GENDRON T F, GRIMA J C, et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins[J]. Nat Neurosci, 2016, 19(5): 668-677.
23	GENDRON T F, BELZIL V V, ZHANG Y J, et al. Mechanisms of toxicity in C9FTLD/ALS[J]. Acta Neuropathol, 2014, 127(3): 359-376.
24	ZHANG K J, WANG A L, ZHONG K K, et al. UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model[J]. Neuron, 2021, 109(12): 1949-1962.e6.
25	TABET R, SCHAEFFER L, FREYERMUTH F, et al. CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts[J]. Nat Commun, 2018, 9(1): 152.
26	GREEN K M, GLINEBURG M R, KEARSE M G, et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response[J]. Nat Commun, 2017, 8(1): 2005.
27	CHENG W W, WANG S P, MESTRE A A, et al. C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation[J]. Nat Commun, 2018, 9(1): 51.
28	CLEARY J D, RANUM L P. New developments in RAN translation: insights from multiple diseases[J]. Curr Opin Genet Dev, 2017, 44: 125-134.
29	WOJCIECHOWSKA M, OLEJNICZAK M, GALKA-MARCINIAK P, et al. RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders[J]. Nucleic Acids Res, 2014, 42(19): 11849-11864.
30	GOODMAN L D, PRUDENCIO M, SRINIVASAN A R, et al. eIF4B and eIF4H mediate GR production from expanded G₄C₂ in a Drosophila model for C9orf72-associated ALS[J]. Acta Neuropathol Commun, 2019, 7(1): 62.
31	COOPER-KNOCK J, WALSH M J, HIGGINBOTTOM A, et al. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions[J]. Brain, 2014, 137(Pt 7): 2040-2051.
32	JODOIN R, CARRIER J C, RIVARD N, et al. G-quadruplex located in the 5' UTR of the BAG-1 mRNA affects both its cap-dependent and cap-independent translation through global secondary structure maintenance[J]. Nucleic Acids Res, 2019, 47(19): 10247-10266.
33	WOLFE A L, SINGH K, ZHONG Y, et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer[J]. Nature, 2014, 513(7516): 65-70.
34	HAEUSLER A R, DONNELLY C J, PERIZ G, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease[J]. Nature, 2014, 507(7491): 195-200.
35	ŠKET P, POHLEVEN J, KOVANDA A, et al. Characterization of DNA G-quadruplex species forming from C9ORF72 G4C2-expanded repeats associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration[J]. Neurobiol Aging, 2015, 36(2): 1091-1096.
36	BRCIC J, PLAVEC J. NMR structure of a G-quadruplex formed by four d(G4C2) repeats: insights into structural polymorphism[J]. Nucleic Acids Res, 2018, 46(21): 11605-11617.
37	SUN Y J, ATAS E, LINDQVIST L, et al. The eukaryotic initiation factor eIF4H facilitates loop-binding, repetitive RNA unwinding by the eIF4A DEAD-box helicase[J]. Nucleic Acids Res, 2012, 40(13): 6199-6207.
38	HARMS U, ANDREOU A Z, GUBAEV A, et al. eIF4B, eIF4G and RNA regulate eIF4A activity in translation initiation by modulating the eIF4A conformational cycle[J]. Nucleic Acids Res, 2014, 42(12): 7911-7922.
39	WESTERGARD T, MCAVOY K, RUSSELL K, et al. Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress[J]. EMBO Mol Med, 2019, 11(2): e9423.
40	ZU T, GUO S, BARDHI O, et al. Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice[J]. Proc Natl Acad Sci USA, 2020, 117(31): 18591-18599.
41	SONOBE Y, GHADGE G, MASAKI K, et al. Translation of dipeptide repeat proteins from the C9ORF72 expanded repeat is associated with cellular stress[J]. Neurobiol Dis, 2018, 116: 155-165.
42	HOLCIK M, SONENBERG N. Translational control in stress and apoptosis[J]. Nat Rev Mol Cell Biol, 2005, 6(4): 318-327.
43	ORTEGA J A, DALEY E L, KOUR S, et al. Nucleocytoplasmic proteomic analysis uncovers eRF1 and nonsense-mediated decay as modifiers of ALS/FTD C9orf72 toxicity[J]. Neuron, 2020, 106(1): 90-107.e13.
44	JOVIČIĆ A, MERTENS J, BOEYNAEMS S, et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS[J]. Nat Neurosci, 2015, 18(9): 1226-1229.
45	KRAMER N J, HANEY M S, MORGENS D W, et al. CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity[J]. Nat Genet, 2018, 50(4): 603-612.
46	MAOR-NOF M, SHIPONY Z, LOPEZ-GONZALEZ R, et al. p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)[J]. Cell, 2021, 184(3): 689-708.e20.
47	BERSON A, GOODMAN L D, SARTORIS A N, et al. Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies[J]. Acta Neuropathol Commun, 2019, 7(1): 65.
48	HAUTBERGUE G M, CASTELLI L M, FERRAIUOLO L, et al. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits[J]. Nat Commun, 2017, 8: 16063.
49	WANG S P, LATALLO M J, ZHANG Z, et al. Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD[J]. Nat Commun, 2021, 12(1): 4908.
50	ZHANG K, DONNELLY C J, HAEUSLER A R, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport[J]. Nature, 2015, 525(7567): 56-61.
51	FREIBAUM B D, LU Y B, LOPEZ-GONZALEZ R, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport[J]. Nature, 2015, 525(7567): 129-133.
52	YAMADA S B, GENDRON T F, NICCOLI T, et al. RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats[J]. Nat Neurosci, 2019, 22(9): 1383-1388.
53	MAO Y H, DONG L M, LIU X M, et al. m⁶A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2[J]. Nat Commun, 2019, 10(1): 5332.
54	SHEN L, PELLETIER J. General and target-specific DExD/H RNA helicases in eukaryotic translation initiation[J]. Int J Mol Sci, 2020, 21(12): E4402.
55	CHENG W W, WANG S P, ZHANG Z, et al. CRISPR-Cas9 screens identify the RNA helicase DDX3X as a repressor of C9ORF72 (GGGGCC)_n repeat-associated non-AUG translation[J]. Neuron, 2019, 104(5): 885-898.e8.
56	LIU H H, LU Y N, PAUL T, et al. A helicase unwinds hexanucleotide repeat RNA G-quadruplexes and facilitates repeat-associated non-AUG translation[J]. J Am Chem Soc, 2021, 143(19): 7368-7379.
57	TSENG Y J, SANDWITH S N, GREEN K M, et al. The RNA helicase DHX36-G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat-associated translation[J]. J Biol Chem, 2021, 297(2): 100914.
58	FRATTA P, MIZIELINSKA S, NICOLL A J, et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes[J]. Sci Rep, 2012, 2: 1016.
59	REDDY K, ZAMIRI B, STANLEY S Y R, et al. The disease-associated r(GGGGCC)_n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures[J]. J Biol Chem, 2013, 288(14): 9860-9866.
60	CONLON E G, LU L, SHARMA A, et al. The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains[J]. Elife, 2016, 5: e17820.
61	SU Z M, ZHANG Y J, GENDRON T F, et al. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS[J]. Neuron, 2014, 83(5): 1043-1050.
62	SIMONE R, BALENDRA R, MOENS T G, et al. G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo[J]. EMBO Mol Med, 2018, 10(1): 22-31.
63	WANG Z F, URSU A, CHILDS-DISNEY J L, et al. The hairpin form of r(G₄C₂)^exp in c9ALS/FTD is repeat-associated non-ATG translated and a target for bioactive small molecules[J]. Cell Chem Biol, 2019, 26(2): 179-190.e12.

[1]	TANG Kairan, WU Qiong, HUANG Sijia, QIU Xudong, LI Wenyan, DENG Huayun, HUANG Lei. Screening of MUCIN family members synergistic with MUC1 in tumor chemoresistance [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(9): 1288-1295.
[2]	CHU Yunkai, LIAO Chunhua, DENG Huayun, HUANG Lei. Study of the regulatory network of MUC1 and tumor-associated proteins [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(8): 1024-1033.
[3]	LIU Hongqiang, LU Yanqing, GAO Yuxuan, WANG Yiyun, WANG Chuandong, ZHANG Xiaoling. Construction of OPEI vector for silencing TRAF6 to promote cartilage regeneration in inflammatory environment [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(7): 846-857.
[4]	ZHAO Jiuhong, TONG Jiating, SHEN Zhijun, LÜ Yehui. Research progress in the mechanism of interactive regulation between circular RNA and oxidative stress [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(3): 393-399.
[5]	CHEN Yiting, ZHAO Anda, LI Rong, KANG Wenhui, LI Shenghui. Review of the role of circulating exosomal microRNA in bronchial asthma [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(3): 375-380.
[6]	Tian-yao SUN, Shi-feng JIANG, Qin XU, Jun-ling LIU, Su-ying DANG, Xue-mei FAN. A novel antithrombotic antibody targeting the binding sites of the coagulation factor FⅨa-FⅧa complex [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(9): 1133-1141.
[7]	Li LIU, Zi-long GENG, Jia-huan CHEN, Sha-sha ZHANG, Bing ZHANG. Whole gene expression profile analysis of miRNAs in human umbilical vein endothelial cells regulated by vascular endothelial growth factor A [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(9): 1183-1189.
[8]	Jing-yan HU, Lin ZHANG, Liang ZHANG. Function of human nucleic acid alkylation damage repair enzyme ALKBH3 in cancer progression and oncotherapy [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(5): 684-689.
[9]	Ze-nan WU, Chen ZHANG. Research advances in inflammatory mechanism of anhedonia [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(2): 241-245.
[10]	HE Ming, WEI Qian, ZHANG Ying-ting. Research progress in the mechanism of ferroptosis and its role in liver related diseases [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(11): 1519-1523.
[11]	WU Ruo-lan, ZHANG Yue, YU Run-hua, DING Ze-yu, HUANG Ying. Effect of protein phosphatase 2A on energy metabolism [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(11): 1530-1535.
[12]	YANG Shuo-yao1, 2, QI Zi-yi3, XIANG Jun4. Research progress of mitochondrial Lon protease and its related diseases [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(5): 683-687.
[13]	QU Guo-jun1, LU Yuan-feng2, LI Yu1. Mechanism of CCT2, a new downstream substrate of PDGFRα, on proliferation of tumor cells [J]. , 2019, 39(1): 28-.
[14]	DONG Rui1, WANG Ying1, WANG Yu-mei1, SUN Zu-jun1, 2, YI Jing1, YANG Jie1. SENP3-mediated de-SUMOylation of p53 inhibits its activity in human lung cancer cell lines [J]. , 2018, 38(7): 732-.
[15]	LIU Jin-quan1, XIE Bing2. Role of BV8 and its antibody in angiogenesis [J]. , 2018, 38(4): 472-.

Initiation and regulatory mechanism of C9ORF72 (G₄C₂)_n RAN translation

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 2

TrendMD

References 63

Related Articles 15

Recommended Articles

Metrics

Comments