Repeat-associated Non-AUG (RAN) Translation: Insights from Pathology

Overview

Journal Lab Invest

Specialty Pathology

Date 2019 Mar 29

PMID 30918326

Citations 24

Authors

Monica Banez-Coronel

Laura P W Ranum

Affiliations

Soon will be listed here.

Abstract

More than 40 different neurological diseases are caused by microsatellite repeat expansions. Since the discovery of repeat-associated non-AUG (RAN) translation by Zu et al. in 2011, nine expansion disorders have been identified as RAN-positive diseases. RAN proteins are translated from different types of nucleotide repeat expansions and can be produced from both sense and antisense transcripts. In some diseases, RAN proteins have been shown to accumulate in affected brain regions. Here we review the pathological and molecular aspects associated with RAN protein accumulation for each particular disorder, the correlation between disease pathology and the available in vivo models and the common aspects shared by some of the newly discovered RAN proteins.

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References

Holmberg M, Duyckaerts C, Durr A, Cancel G, Gourfinkel-An I, Damier P . Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet. 1998; 7(5):913-8. DOI: 10.1093/hmg/7.5.913. View

Ohki Y, Wenninger-Weinzierl A, Hruscha A, Asakawa K, Kawakami K, Haass C . Glycine-alanine dipeptide repeat protein contributes to toxicity in a zebrafish model of C9orf72 associated neurodegeneration. Mol Neurodegener. 2017; 12(1):6. PMC: 5237533. DOI: 10.1186/s13024-016-0146-8. View

Batra R, Charizanis K, Swanson M . Partners in crime: bidirectional transcription in unstable microsatellite disease. Hum Mol Genet. 2010; 19(R1):R77-82. PMC: 2875054. DOI: 10.1093/hmg/ddq132. View

Rees E, Farmer R, Cole J, Haider S, Durr A, Landwehrmeyer B . Cerebellar abnormalities in Huntington's disease: a role in motor and psychiatric impairment?. Mov Disord. 2014; 29(13):1648-54. DOI: 10.1002/mds.25984. View

Zerylnick C, Torroni A, Sherman S, Warren S . Normal variation at the myotonic dystrophy locus in global human populations. Am J Hum Genet. 1995; 56(1):123-30. PMC: 1801327. View

Freibaum B, Lu Y, Lopez-Gonzalez R, Kim N, Almeida S, Lee K . GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015; 525(7567):129-33. PMC: 4631399. DOI: 10.1038/nature14974. View

La Spada A, Taylor J . Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet. 2010; 11(4):247-58. PMC: 4704680. DOI: 10.1038/nrg2748. View

Nolin S, Brown W, Glicksman A, Houck Jr G, Gargano A, Sullivan A . Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet. 2003; 72(2):454-64. PMC: 379237. DOI: 10.1086/367713. View

Renton A, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs J . A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011; 72(2):257-68. PMC: 3200438. DOI: 10.1016/j.neuron.2011.09.010. View

10.

ORourke J, Bogdanik L, Muhammad A, Gendron T, Kim K, Austin A . C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD. Neuron. 2015; 88(5):892-901. PMC: 4672384. DOI: 10.1016/j.neuron.2015.10.027. View

11.

Ebbert M, Farrugia S, Sens J, Jansen-West K, Gendron T, Prudencio M . Long-read sequencing across the C9orf72 'GGGGCC' repeat expansion: implications for clinical use and genetic discovery efforts in human disease. Mol Neurodegener. 2018; 13(1):46. PMC: 6102925. DOI: 10.1186/s13024-018-0274-4. View

12.

Paulson H . Repeat expansion diseases. Handb Clin Neurol. 2018; 147:105-123. PMC: 6485936. DOI: 10.1016/B978-0-444-63233-3.00009-9. View

13.

Sofola O, Jin P, Qin Y, Duan R, Liu H, de Haro M . RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron. 2007; 55(4):565-71. PMC: 2215388. DOI: 10.1016/j.neuron.2007.07.021. View

14.

Lee J, Cooper T . Pathogenic mechanisms of myotonic dystrophy. Biochem Soc Trans. 2009; 37(Pt 6):1281-6. PMC: 3873089. DOI: 10.1042/BST0371281. View

15.

Zhang Y, Gendron T, Ebbert M, ORaw A, Yue M, Jansen-West K . Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat Med. 2018; 24(8):1136-1142. PMC: 6520050. DOI: 10.1038/s41591-018-0071-1. View

16.

Sakae N, Bieniek K, Zhang Y, Ross K, Gendron T, Murray M . Poly-GR dipeptide repeat polymers correlate with neurodegeneration and Clinicopathological subtypes in C9ORF72-related brain disease. Acta Neuropathol Commun. 2018; 6(1):63. PMC: 6054740. DOI: 10.1186/s40478-018-0564-7. View

17.

Ranum L, Daughters R, Tuttle D, Gao W, Ikeda Y, Moseley M . [Double the trouble: bidirectional expression of the SCA8 CAG/CTG expansion mutation - evidence for RNA and protein gain of function effects]. Rinsho Shinkeigaku. 2011; 50(11):982-3. DOI: 10.5692/clinicalneurol.50.982. View

18.

Westergard T, Jensen B, Wen X, Cai J, Kropf E, Iacovitti L . Cell-to-Cell Transmission of Dipeptide Repeat Proteins Linked to C9orf72-ALS/FTD. Cell Rep. 2016; 17(3):645-652. PMC: 5078984. DOI: 10.1016/j.celrep.2016.09.032. View

19.

Moens T, Niccoli T, Wilson K, Atilano M, Birsa N, Gittings L . C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A. Acta Neuropathol. 2019; 137(3):487-500. PMC: 6514073. DOI: 10.1007/s00401-018-1946-4. View

20.

Buijsen R, Visser J, Kramer P, Severijnen E, Gearing M, Charlet-Berguerand N . Presence of inclusions positive for polyglycine containing protein, FMRpolyG, indicates that repeat-associated non-AUG translation plays a role in fragile X-associated primary ovarian insufficiency. Hum Reprod. 2015; 31(1):158-68. PMC: 4677964. DOI: 10.1093/humrep/dev280. View