Abnormal RNA translation and amyotrophic lateral sclerosis_West China Medical Journal

Authors：

ZHANG Xinyi , SHANG Huifang ,  WEI Qianqian

Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

WEI Qianqian, Email: 578361552@qq.com

Keywords：

Amyotrophic lateral sclerosis; motor neuron disease; RNA translation; integrated stress response

DOI：

10.7507/1002-0179.202404278

Video：

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Abstract Full text Figures/Tables Video References Cited by

The translation and translation regulation of RNA in eukaryotic cells have a significant impact on cellular gene expression and maintenance of proteomic homeostasis. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper and lower motor neurons and leads to muscle weakness and atrophy. More and more studies have found RNA translation abnormalities in ALS. This article provides an overview of RNA translation and regulation in eukaryotic cells under physiological and stress conditions, and explores the relationship between four different ALS-related genes and translation abnormalities, providing new ideas for the treatment of ALS.

1.	Hershey JWB, Sonenberg N, Mathews MB. Principles of translational control. Cold Spring Harb Perspect Biol, 2019, 11(9): a032607.
2.	Guo S, Nguyen L, Ranum LPW. RAN proteins in neurodegenerative disease: repeating themes and unifying therapeutic strategies. Curr Opin Neurobiol, 2022, 72: 160-170.
3.	Smith MR, Costa G. RNA-binding proteins and translation control in angiogenesis. FEBS J, 2022, 289(24): 7788-7809.
4.	Weidemüller P, Kholmatov M, Petsalaki E, et al. Transcription factors: bridge between cell signaling and gene regulation. Proteomics, 2021, 21(23/24): e2000034.
5.	Wolozin B, Ivanov P. Stress granules and neurodegeneration. Nat Rev Neurosci, 2019, 20(11): 649-666.
6.	Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol, 2020, 21(8): 421-438.
7.	Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med, 2017, 377(2): 162-172.
8.	Akçimen F, Lopez ER, Landers JE, et al. Amyotrophic lateral sclerosis: translating genetic discoveries into therapies. Nat Rev Genet, 2023, 24(9): 642-658.
9.	Goutman SA, Hardiman O, Al-Chalabi A, et al. Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis. Lancet Neurol, 2022, 21(5): 465-479.
10.	Storkebaum E, Rosenblum K, Sonenberg N. Messenger RNA translation defects in neurodegenerative diseases. N Engl J Med, 2023, 388(11): 1015-1030.
11.	Krishnan G, Raitcheva D, Bartlett D, et al. Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD. Nat Commun, 2022, 13(1): 2799.
12.	Popper B, Scheidt T, Schieweck R. RNA-binding protein dysfunction in neurodegeneration. Essays Biochem, 2021, 65(7): 975-986.
13.	Glock C, Biever A, Tushev G, et al. The translatome of neuronal cell bodies, dendrites, and axons. Proc Natl Acad Sci USA, 2021, 118(43): e2113929118.
14.	Dever TE, Green R. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb Perspect Biol, 2012, 4(7): a013706.
15.	Castelli LM, Huang WP, Lin YH, et al. Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders. Biochem Soc Trans, 2021, 49(2): 775-792.
16.	Malik I, Kelley CP, Wang ET, et al. Molecular mechanisms underlying nucleotide repeat expansion disorders. Nat Rev Mol Cell Biol, 2021, 22(9): 589-607.
17.	Mori K, Gotoh S, Ikeda M. Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA. J Neurochem, 2023, 166(2): 156-171.
18.	Khalil B, Morderer D, Price PL, et al. mRNP assembly, axonal transport, and local translation in neurodegenerative diseases. Brain Res, 2018, 1693(Pt A): 75-91.
19.	Blanco-Urrejola M, Gaminde-Blasco A, Gamarra M, et al. RNA localization and local translation in glia in neurological and neurodegenerative diseases: lessons from neurons. Cells, 2021, 10(3): 632.
20.	Buxbaum AR, Haimovich G, Singer RH. In the right place at the right time: visualizing and understanding mRNA localization. Nat Rev Mol Cell Biol, 2015, 16(2): 95-109.
21.	Das S, Vera M, Gandin V, et al. Intracellular mRNA transport and localized translation. Nat Rev Mol Cell Biol, 2021, 22(7): 483-504.
22.	Pino MG, Rich KA, Hall NJ, et al. Heterogeneous splicing patterns resulting from KIF5A variants associated with amyotrophic lateral sclerosis. Hum Mol Genet, 2023, 32(22): 3166-3180.
23.	Baron DM, Fenton AR, Saez-Atienzar S, et al. ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function. Cell Rep, 2022, 39(1): 110598.
24.	Perea V, Baron KR, Dolina V, et al. Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells. Cell Chem Biol, 2023, 30(12): 1571-1584. e5.
25.	Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science, 2020, 368(6489): eaat5314.
26.	Bond S, Lopez-Lloreda C, Gannon PJ, et al. The integrated stress response and phosphorylated eukaryotic initiation factor 2α in neurodegeneration. J Neuropathol Exp Neurol, 2020, 79(2): 123-143.
27.	Ashraf D, Khan MR, Dawson TM, et al. Protein translation in the pathogenesis of Parkinson’s disease. Int J Mol Sci, 2024, 25(4): 2393.
28.	Derisbourg MJ, Hartman MD, Denzel MS. Perspective: modulating the integrated stress response to slow aging and ameliorate age-related pathology. Nat Aging, 2021, 1(9): 760-768.
29.	Oliveira MM, Lourenco MV, Longo F, et al. Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease. Sci Signal, 2021, 14(668): eabc5429.
30.	Craig RA 2nd, De Vicente J, Estrada AA, et al. Discovery of DNL343: a potent, selective, and brain-penetrant eIF2B activator designed for the treatment of neurodegenerative diseases. J Med Chem, 2024, 67(7): 5758-5782.
31.	Szewczyk B, Günther R, Japtok J, et al. FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration. Cell Rep, 2023, 42(2): 112025.
32.	Marlin E, Valencia M, Peregrín N, et al. Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model. Br J Pharmacol, 2024, 181(3): 495-508.
33.	Pun S, Santos AF, Saxena S, et al. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci, 2006, 9(3): 408-419.
34.	Saxena S, Cabuy E, Caroni P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci, 2009, 12(5): 627-636.
35.	Nishitoh H, Kadowaki H, Nagai A, et al. ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting derlin-1. Genes Dev, 2008, 22(11): 1451-1464.
36.	Das I, Krzyzosiak A, Schneider K, et al. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science, 2015, 348(6231): 239-242.
37.	Dalla Bella E, Bersano E, Antonini G, et al. The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial. Brain, 2021, 144(9): 2635-2647.
38.	Tabet R, Schaeffer L, Freyermuth F, et al. CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts. Nat Commun, 2018, 9(1): 152.
39.	Green KM, Glineburg MR, Kearse MG, et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat Commun, 2017, 8(1): 2005.
40.	Cheng W, Wang S, Mestre AA, et al. C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nat Commun, 2018, 9(1): 51.
41.	Shatsky IN, Terenin IM, Smirnova VV, et al. Cap-independent translation: what’s in a name?. Trends Biochem Sci, 2018, 43(11): 882-895.
42.	Hertz MI, Landry DM, Willis AE, et al. Ribosomal protein S25 dependency reveals a common mechanism for diverse internal ribosome entry sites and ribosome shunting. Mol Cell Biol, 2013, 33(5): 1016-1026.
43.	Nishiyama T, Yamamoto H, Uchiumi T, et al. Eukaryotic ribosomal protein RPS25 interacts with the conserved loop region in a dicistroviral intergenic internal ribosome entry site. Nucleic Acids Res, 2007, 35(5): 1514-1521.
44.	Yamada SB, Gendron TF, Niccoli T, et al. RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats. Nat Neurosci, 2019, 22(9): 1383-1388.
45.	Sonobe Y, Aburas J, Krishnan G, et al. A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation. Nat Commun, 2021, 12(1): 6025.
46.	Goodman LD, Prudencio M, Srinivasan AR, et al. eIF4B and eIF4H mediate GR production from expanded G4C2 in a drosophila model for C9orf72-associated ALS. Acta Neuropathol Commun, 2019, 7(1): 62.
47.	Fratta P, Mizielinska S, Nicoll AJ, et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep, 2012, 2: 1016.
48.	Su Z, Zhang Y, Gendron TF, et al. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron, 2014, 83(5): 1043-1050.
49.	Cheng W, Wang S, Zhang Z, et al. CRISPR-cas9 screens identify the RNA helicase DDX3X as a repressor of C9ORF72 (GGGGCC)n repeat-associated non-AUG translation. Neuron, 2019, 104(5): 885-898.e8.
50.	Liu H, Lu YN, Paul T, et al. A helicase unwinds hexanucleotide repeat RNA G-quadruplexes and facilitates repeat-associated non-AUG translation. J Am Chem Soc, 2021, 143(19): 7368-7379.
51.	Tseng YJ, Sandwith SN, Green KM, et al. The RNA helicase DHX36-G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat-associated translation. J Biol Chem, 2021, 297(2): 100914.
52.	Zu T, Guo S, Bardhi O, et al. Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proc Natl Acad Sci USA, 2020, 117(31): 18591-18599.
53.	Westergard T, McAvoy K, Russell K, et al. Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress. EMBO Mol Med, 2019, 11(2): e9423.
54.	Licata NV, Cristofani R, Salomonsson S, et al. C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation. EMBO J, 2022, 41(1): e105026.
55.	Smeele PH, Cesare G, Vaccari T. ALS’ perfect storm: C9orf72-associated toxic dipeptide repeats as potential multipotent disruptors of protein homeostasis. Cells, 2024, 13(2): 178.
56.	Loveland AB, Svidritskiy E, Susorov D, et al. Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM. Nat Commun, 2022, 13(1): 2776.
57.	Moens TG, Niccoli T, Wilson KM, et al. 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.
58.	Korobeynikov VA, Lyashchenko AK, Blanco-Redondo B, et al. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med, 2022, 28(1): 104-116.
59.	Portz B, Lee BL, Shorter J. FUS and TDP-43 phases in health and disease. Trends Biochem Sci, 2021, 46(7): 550-563.
60.	Reber S, Jutzi D, Lindsay H, et al. The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid-liquid phase separation. Nucleic Acids Res, 2021, 49(13): 7713-7731.
61.	Birsa N, Ule AM, Garone MG, et al. FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation. Sci Adv, 2021, 7(30): eabf8660.
62.	An H, Litscher G, Watanabe N, et al. ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity. Neurobiol Dis, 2022, 162: 105585.
63.	López-Erauskin J, Tadokoro T, Baughn MW, et al. ALS/FTD-linked mutation in FUS suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS. Neuron, 2018, 100(4): 816-830.e7.
64.	McMillan M, Gomez N, Hsieh C, et al. RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia. Mol Cell, 2023, 83(2): 219-236.e7.
65.	Ziff OJ, Neeves J, Mitchell J, et al. Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology. Nat Commun, 2023, 14(1): 2176.
66.	Tank EM, Figueroa-Romero C, Hinder LM, et al. Abnormal RNA stability in amyotrophic lateral sclerosis. Nat Commun, 2018, 9(1): 2845.
67.	Hallegger M, Chakrabarti AM, Lee FCY, et al. TDP-43 condensation properties specify its RNA-binding and regulatory repertoire. Cell, 2021, 184(18): 4680-4696.e22.
68.	Baughn MW, Melamed Z, López-Erauskin J, et al. Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science, 2023, 379(6637): 1140-1149.
69.	Gao J, Wang L, Ren X, et al. Translational regulation in the brain by TDP-43 phase separation. J Cell Biol, 2021, 220(10): e202101019.
70.	Markmiller S, Sathe S, Server KL, et al. Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress. Cell Rep, 2021, 36(10): 109685.
71.	Zuo X, Zhou J, Li Y, et al. TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS. Nat Struct Mol Biol, 2021, 28(2): 132-142.

1. Hershey JWB, Sonenberg N, Mathews MB. Principles of translational control. Cold Spring Harb Perspect Biol, 2019, 11(9): a032607.
2. Guo S, Nguyen L, Ranum LPW. RAN proteins in neurodegenerative disease: repeating themes and unifying therapeutic strategies. Curr Opin Neurobiol, 2022, 72: 160-170.
3. Smith MR, Costa G. RNA-binding proteins and translation control in angiogenesis. FEBS J, 2022, 289(24): 7788-7809.
4. Weidemüller P, Kholmatov M, Petsalaki E, et al. Transcription factors: bridge between cell signaling and gene regulation. Proteomics, 2021, 21(23/24): e2000034.
5. Wolozin B, Ivanov P. Stress granules and neurodegeneration. Nat Rev Neurosci, 2019, 20(11): 649-666.
6. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol, 2020, 21(8): 421-438.
7. Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med, 2017, 377(2): 162-172.
8. Akçimen F, Lopez ER, Landers JE, et al. Amyotrophic lateral sclerosis: translating genetic discoveries into therapies. Nat Rev Genet, 2023, 24(9): 642-658.
9. Goutman SA, Hardiman O, Al-Chalabi A, et al. Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis. Lancet Neurol, 2022, 21(5): 465-479.
10. Storkebaum E, Rosenblum K, Sonenberg N. Messenger RNA translation defects in neurodegenerative diseases. N Engl J Med, 2023, 388(11): 1015-1030.
11. Krishnan G, Raitcheva D, Bartlett D, et al. Poly(GR) and poly(GA) in cerebrospinal fluid as potential biomarkers for C9ORF72-ALS/FTD. Nat Commun, 2022, 13(1): 2799.
12. Popper B, Scheidt T, Schieweck R. RNA-binding protein dysfunction in neurodegeneration. Essays Biochem, 2021, 65(7): 975-986.
13. Glock C, Biever A, Tushev G, et al. The translatome of neuronal cell bodies, dendrites, and axons. Proc Natl Acad Sci USA, 2021, 118(43): e2113929118.
14. Dever TE, Green R. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb Perspect Biol, 2012, 4(7): a013706.
15. Castelli LM, Huang WP, Lin YH, et al. Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders. Biochem Soc Trans, 2021, 49(2): 775-792.
16. Malik I, Kelley CP, Wang ET, et al. Molecular mechanisms underlying nucleotide repeat expansion disorders. Nat Rev Mol Cell Biol, 2021, 22(9): 589-607.
17. Mori K, Gotoh S, Ikeda M. Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA. J Neurochem, 2023, 166(2): 156-171.
18. Khalil B, Morderer D, Price PL, et al. mRNP assembly, axonal transport, and local translation in neurodegenerative diseases. Brain Res, 2018, 1693(Pt A): 75-91.
19. Blanco-Urrejola M, Gaminde-Blasco A, Gamarra M, et al. RNA localization and local translation in glia in neurological and neurodegenerative diseases: lessons from neurons. Cells, 2021, 10(3): 632.
20. Buxbaum AR, Haimovich G, Singer RH. In the right place at the right time: visualizing and understanding mRNA localization. Nat Rev Mol Cell Biol, 2015, 16(2): 95-109.
21. Das S, Vera M, Gandin V, et al. Intracellular mRNA transport and localized translation. Nat Rev Mol Cell Biol, 2021, 22(7): 483-504.
22. Pino MG, Rich KA, Hall NJ, et al. Heterogeneous splicing patterns resulting from KIF5A variants associated with amyotrophic lateral sclerosis. Hum Mol Genet, 2023, 32(22): 3166-3180.
23. Baron DM, Fenton AR, Saez-Atienzar S, et al. ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function. Cell Rep, 2022, 39(1): 110598.
24. Perea V, Baron KR, Dolina V, et al. Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells. Cell Chem Biol, 2023, 30(12): 1571-1584. e5.
25. Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science, 2020, 368(6489): eaat5314.
26. Bond S, Lopez-Lloreda C, Gannon PJ, et al. The integrated stress response and phosphorylated eukaryotic initiation factor 2α in neurodegeneration. J Neuropathol Exp Neurol, 2020, 79(2): 123-143.
27. Ashraf D, Khan MR, Dawson TM, et al. Protein translation in the pathogenesis of Parkinson’s disease. Int J Mol Sci, 2024, 25(4): 2393.
28. Derisbourg MJ, Hartman MD, Denzel MS. Perspective: modulating the integrated stress response to slow aging and ameliorate age-related pathology. Nat Aging, 2021, 1(9): 760-768.
29. Oliveira MM, Lourenco MV, Longo F, et al. Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease. Sci Signal, 2021, 14(668): eabc5429.
30. Craig RA 2nd, De Vicente J, Estrada AA, et al. Discovery of DNL343: a potent, selective, and brain-penetrant eIF2B activator designed for the treatment of neurodegenerative diseases. J Med Chem, 2024, 67(7): 5758-5782.
31. Szewczyk B, Günther R, Japtok J, et al. FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration. Cell Rep, 2023, 42(2): 112025.
32. Marlin E, Valencia M, Peregrín N, et al. Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model. Br J Pharmacol, 2024, 181(3): 495-508.
33. Pun S, Santos AF, Saxena S, et al. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci, 2006, 9(3): 408-419.
34. Saxena S, Cabuy E, Caroni P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci, 2009, 12(5): 627-636.
35. Nishitoh H, Kadowaki H, Nagai A, et al. ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting derlin-1. Genes Dev, 2008, 22(11): 1451-1464.
36. Das I, Krzyzosiak A, Schneider K, et al. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science, 2015, 348(6231): 239-242.
37. Dalla Bella E, Bersano E, Antonini G, et al. The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial. Brain, 2021, 144(9): 2635-2647.
38. Tabet R, Schaeffer L, Freyermuth F, et al. CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts. Nat Commun, 2018, 9(1): 152.
39. Green KM, Glineburg MR, Kearse MG, et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat Commun, 2017, 8(1): 2005.
40. Cheng W, Wang S, Mestre AA, et al. C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nat Commun, 2018, 9(1): 51.
41. Shatsky IN, Terenin IM, Smirnova VV, et al. Cap-independent translation: what’s in a name?. Trends Biochem Sci, 2018, 43(11): 882-895.
42. Hertz MI, Landry DM, Willis AE, et al. Ribosomal protein S25 dependency reveals a common mechanism for diverse internal ribosome entry sites and ribosome shunting. Mol Cell Biol, 2013, 33(5): 1016-1026.
43. Nishiyama T, Yamamoto H, Uchiumi T, et al. Eukaryotic ribosomal protein RPS25 interacts with the conserved loop region in a dicistroviral intergenic internal ribosome entry site. Nucleic Acids Res, 2007, 35(5): 1514-1521.
44. Yamada SB, Gendron TF, Niccoli T, et al. RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats. Nat Neurosci, 2019, 22(9): 1383-1388.
45. Sonobe Y, Aburas J, Krishnan G, et al. A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation. Nat Commun, 2021, 12(1): 6025.
46. Goodman LD, Prudencio M, Srinivasan AR, et al. eIF4B and eIF4H mediate GR production from expanded G4C2 in a drosophila model for C9orf72-associated ALS. Acta Neuropathol Commun, 2019, 7(1): 62.
47. Fratta P, Mizielinska S, Nicoll AJ, et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep, 2012, 2: 1016.
48. Su Z, Zhang Y, Gendron TF, et al. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron, 2014, 83(5): 1043-1050.
49. Cheng W, Wang S, Zhang Z, et al. CRISPR-cas9 screens identify the RNA helicase DDX3X as a repressor of C9ORF72 (GGGGCC)n repeat-associated non-AUG translation. Neuron, 2019, 104(5): 885-898.e8.
50. Liu H, Lu YN, Paul T, et al. A helicase unwinds hexanucleotide repeat RNA G-quadruplexes and facilitates repeat-associated non-AUG translation. J Am Chem Soc, 2021, 143(19): 7368-7379.
51. Tseng YJ, Sandwith SN, Green KM, et al. The RNA helicase DHX36-G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat-associated translation. J Biol Chem, 2021, 297(2): 100914.
52. Zu T, Guo S, Bardhi O, et al. Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proc Natl Acad Sci USA, 2020, 117(31): 18591-18599.
53. Westergard T, McAvoy K, Russell K, et al. Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress. EMBO Mol Med, 2019, 11(2): e9423.
54. Licata NV, Cristofani R, Salomonsson S, et al. C9orf72 ALS/FTD dipeptide repeat protein levels are reduced by small molecules that inhibit PKA or enhance protein degradation. EMBO J, 2022, 41(1): e105026.
55. Smeele PH, Cesare G, Vaccari T. ALS’ perfect storm: C9orf72-associated toxic dipeptide repeats as potential multipotent disruptors of protein homeostasis. Cells, 2024, 13(2): 178.
56. Loveland AB, Svidritskiy E, Susorov D, et al. Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM. Nat Commun, 2022, 13(1): 2776.
57. Moens TG, Niccoli T, Wilson KM, et al. 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.
58. Korobeynikov VA, Lyashchenko AK, Blanco-Redondo B, et al. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. Nat Med, 2022, 28(1): 104-116.
59. Portz B, Lee BL, Shorter J. FUS and TDP-43 phases in health and disease. Trends Biochem Sci, 2021, 46(7): 550-563.
60. Reber S, Jutzi D, Lindsay H, et al. The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid-liquid phase separation. Nucleic Acids Res, 2021, 49(13): 7713-7731.
61. Birsa N, Ule AM, Garone MG, et al. FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation. Sci Adv, 2021, 7(30): eabf8660.
62. An H, Litscher G, Watanabe N, et al. ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity. Neurobiol Dis, 2022, 162: 105585.
63. López-Erauskin J, Tadokoro T, Baughn MW, et al. ALS/FTD-linked mutation in FUS suppresses intra-axonal protein synthesis and drives disease without nuclear loss-of-function of FUS. Neuron, 2018, 100(4): 816-830.e7.
64. McMillan M, Gomez N, Hsieh C, et al. RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia. Mol Cell, 2023, 83(2): 219-236.e7.
65. Ziff OJ, Neeves J, Mitchell J, et al. Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology. Nat Commun, 2023, 14(1): 2176.
66. Tank EM, Figueroa-Romero C, Hinder LM, et al. Abnormal RNA stability in amyotrophic lateral sclerosis. Nat Commun, 2018, 9(1): 2845.
67. Hallegger M, Chakrabarti AM, Lee FCY, et al. TDP-43 condensation properties specify its RNA-binding and regulatory repertoire. Cell, 2021, 184(18): 4680-4696.e22.
68. Baughn MW, Melamed Z, López-Erauskin J, et al. Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science, 2023, 379(6637): 1140-1149.
69. Gao J, Wang L, Ren X, et al. Translational regulation in the brain by TDP-43 phase separation. J Cell Biol, 2021, 220(10): e202101019.
70. Markmiller S, Sathe S, Server KL, et al. Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress. Cell Rep, 2021, 36(10): 109685.
71. Zuo X, Zhou J, Li Y, et al. TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS. Nat Struct Mol Biol, 2021, 28(2): 132-142.

West China Medical Journal

Latest ArticlesAbnormal RNA translation and amyotrophic lateral sclerosis

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