DDX3X overexpression decreases dipeptide repeat proteins in a mouse model of C9ORF72-ALS/FTD

Xiujuan Fu; Zhe Zhang; Lindsey R Hayes; Noelle Wright; Julie Asbury; Shelley Li; Yingzhi Ye; Shuying Sun

doi:10.1016/j.expneurol.2024.114768

DDX3X overexpression decreases dipeptide repeat proteins in a mouse model of C9ORF72-ALS/FTD

Exp Neurol. 2024 Jun:376:114768. doi: 10.1016/j.expneurol.2024.114768. Epub 2024 Mar 29.

Authors

Xiujuan Fu¹, Zhe Zhang¹, Lindsey R Hayes², Noelle Wright¹, Julie Asbury³, Shelley Li⁴, Yingzhi Ye⁵, Shuying Sun⁶

Affiliations

¹ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Notre Dame of Maryland University, Baltimore, MD 21210, USA.
⁴ John Hopkins University, Baltimore, MD 21218, USA.
⁵ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Physiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: [email protected].

PMID: 38556190
PMCID: PMC11058010 (available on 2025-06-01)
DOI: 10.1016/j.expneurol.2024.114768

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.

Keywords: ALS; C9ORF72; FTD; Repeat expansion.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Amyotrophic Lateral Sclerosis* / pathology
Animals
C9orf72 Protein* / genetics
C9orf72 Protein* / metabolism
DEAD-box RNA Helicases* / genetics
DEAD-box RNA Helicases* / metabolism
DNA Repeat Expansion / genetics
Dipeptides / metabolism
Disease Models, Animal*
Frontotemporal Dementia* / genetics
Frontotemporal Dementia* / metabolism
Frontotemporal Dementia* / pathology
Humans
Male
Mice
Mice, Transgenic

Substances

C9orf72 Protein
Ddx3x protein, mouse
DEAD-box RNA Helicases
Dipeptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding