DDX3X Overexpression Decreases Dipeptide Repeat Proteins in a Mouse Model of C9ORF72-ALS/FTD

Overview

Journal Exp Neurol

Specialty Neurology

Date 2024 Mar 31

PMID 38556190

Authors

Xiujuan Fu

Zhe Zhang

Lindsey R Hayes

Noelle Wright

Julie Asbury

Shelley Li

Yingzhi Ye

Shuying Sun

Affiliations

Soon will be listed here.

Abstract

Hexanucleotide repeat expansion in C9ORF72 (C9) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One of the proposed pathogenic mechanisms is the neurotoxicity arising from dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG (RAN) translation. Therefore, reducing DPR levels emerges as a potential therapeutic strategy for C9ORF72-ALS/FTD. We previously identified an RNA helicase, DEAD-box helicase 3 X-linked (DDX3X), modulates RAN translation. DDX3X overexpression decreases poly-GP accumulation in C9ORF72-ALS/FTD patient-derived induced pluripotent stem cell (iPSC)-differentiated neurons (iPSNs) and reduces the glutamate-induced neurotoxicity. In this study, we examined the in vivo efficacy of DDX3X overexpression using a mouse model. We expressed exogenous DDX3X or GFP in the central nervous system (CNS) of the C9-500 ALS/FTD BAC transgenic or non-transgenic control mice using adeno-associated virus serotype 9 (AAV9). The DPR levels were significantly reduced in the brains of DDX3X-expressing C9-BAC mice compared to the GFP control even twelve months after virus delivery. Additionally, p62 aggregation was also decreased. No neuronal loss or neuroinflammatory response were detected in the DDX3X overexpressing C9-BAC mice. This work demonstrates that DDX3X overexpression effectively reduces DPR levels in vivo without provoking neuroinflammation or neurotoxicity, suggesting the potential of increasing DDX3X expression as a therapeutic strategy for C9ORF72-ALS/FTD.

Citing Articles

The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.

Jiang S, Xu R Mol Neurobiol. 2024; 62(1):221-232.

PMID: 38829511 DOI: 10.1007/s12035-024-04269-3.

References

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

Chew J, Gendron T, Prudencio M, Sasaguri H, Zhang Y, Castanedes-Casey M . Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science. 2015; 348(6239):1151-4. PMC: 4692360. DOI: 10.1126/science.aaa9344. View

Cheng W, Wang S, Zhang Z, Morgens D, Hayes L, Lee S . 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. PMC: 6895427. DOI: 10.1016/j.neuron.2019.09.003. View

Liu Y, Pattamatta A, Zu T, Reid T, Bardhi O, Borchelt D . C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD. Neuron. 2016; 90(3):521-34. DOI: 10.1016/j.neuron.2016.04.005. View

Zhang Y, Jansen-West K, Xu Y, Gendron T, Bieniek K, Lin W . Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol. 2014; 128(4):505-24. PMC: 4159567. DOI: 10.1007/s00401-014-1336-5. View

Kanekura K, Yagi T, Cammack A, Mahadevan J, Kuroda M, Harms M . Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation. Hum Mol Genet. 2016; 25(9):1803-13. PMC: 4986334. DOI: 10.1093/hmg/ddw052. View

Lee K, Zhang P, Kim H, Mitrea D, Sarkar M, Freibaum B . C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles. Cell. 2016; 167(3):774-788.e17. PMC: 5079111. DOI: 10.1016/j.cell.2016.10.002. View

Dufour B, Smith C, Clark R, Walker T, McBride J . Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in Huntington's disease mice. Mol Ther. 2014; 22(4):797-810. PMC: 3982495. DOI: 10.1038/mt.2013.289. View

Zhang Y, Gendron T, Grima J, Sasaguri H, Jansen-West K, Xu Y . C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat Neurosci. 2016; 19(5):668-677. PMC: 5138863. DOI: 10.1038/nn.4272. View

10.

Martier R, Liefhebber J, Garcia-Osta A, Miniarikova J, Cuadrado-Tejedor M, Espelosin M . Targeting RNA-Mediated Toxicity in C9orf72 ALS and/or FTD by RNAi-Based Gene Therapy. Mol Ther Nucleic Acids. 2019; 16:26-37. PMC: 6393708. DOI: 10.1016/j.omtn.2019.02.001. View

11.

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

12.

Soulat D, Burckstummer T, Westermayer S, Goncalves A, Bauch A, Stefanovic A . The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. EMBO J. 2008; 27(15):2135-46. PMC: 2453059. DOI: 10.1038/emboj.2008.126. View

13.

Mori K, Arzberger T, Grasser F, Gijselinck I, May S, Rentzsch K . Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol. 2013; 126(6):881-93. DOI: 10.1007/s00401-013-1189-3. View

14.

Hsiung G, DeJesus-Hernandez M, Feldman H, Sengdy P, Bouchard-Kerr P, Dwosh E . Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain. 2012; 135(Pt 3):709-22. PMC: 3286328. DOI: 10.1093/brain/awr354. View

15.

Hoy S . Onasemnogene Abeparvovec: First Global Approval. Drugs. 2019; 79(11):1255-1262. DOI: 10.1007/s40265-019-01162-5. View

16.

Nguyen L, Laboissonniere L, Guo S, Pilotto F, Scheidegger O, Oestmann A . Survival and Motor Phenotypes in FVB C9-500 ALS/FTD BAC Transgenic Mice Reproduced by Multiple Labs. Neuron. 2020; 108(4):784-796.e3. PMC: 8281452. DOI: 10.1016/j.neuron.2020.09.009. View

17.

Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I . p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 2011; 122(6):691-702. DOI: 10.1007/s00401-011-0911-2. View

18.

Mo J, Liang H, Su C, Li P, Chen J, Zhang B . DDX3X: structure, physiologic functions and cancer. Mol Cancer. 2021; 20(1):38. PMC: 7903766. DOI: 10.1186/s12943-021-01325-7. View

19.

Hao Z, Liu L, Tao Z, Wang R, Ren H, Sun H . Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR. Nat Commun. 2019; 10(1):2906. PMC: 6606620. DOI: 10.1038/s41467-019-10956-w. View

20.

Jensen B, Schuldi M, McAvoy K, Russell K, Boehringer A, Curran B . Synaptic dysfunction induced by glycine-alanine dipeptides in C9orf72-ALS/FTD is rescued by SV2 replenishment. EMBO Mol Med. 2020; 12(5):e10722. PMC: 7207170. DOI: 10.15252/emmm.201910722. View