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RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer's disease
Genís Campoy-Campos1,2, Julia Solana-Balaguer1,2, Anna Guisado-Corcoll1,2,3
1Departament de Biomedicina, Institut de Neurociències, Universitat de Barcelona, Barcelona 08036, Catalonia, Spain.
Nucleic Acids Research
|September 13, 2024
Summary
Elevated RTP801/REDD1 protein impairs RNA processing in Alzheimer's disease (AD). Silencing RTP801 restores RNA processing and prevents neuronal abnormalities, suggesting RTP801 inhibition as a potential AD therapy.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- RTP801/REDD1 is a stress-responsive protein implicated in neurodegenerative diseases like Alzheimer's disease (AD).
- RTP801 contributes to cognitive deficits and neuroinflammation in AD.
- The unfolded protein response (UPR) involves RNA processing by the tRNA ligase complex (tRNA-LC).
Purpose of the Study:
- To investigate the interaction between RTP801 and the tRNA ligase complex (tRNA-LC).
- To determine the role of RTP801 in RNA processing, specifically XBP1 splicing, in the context of AD.
- To evaluate the therapeutic potential of targeting RTP801 in AD.
Main Methods:
- Investigated RTP801 interaction with tRNA-LC components (HSPC117, DDX1, CGI-99).
- Assessed RTP801's effect on XBP1 splicing in vitro and in human AD postmortem samples.
- Utilized a 5xFAD mouse model of AD to study RTP801 silencing effects on RNA processing and neuronal morphology.
Main Results:
- RTP801 interacts with HSPC117, DDX1, and CGI-99, members of the tRNA-LC.
- RTP801 knockdown promoted XBP1 splicing, while RTP801 overexpression inhibited it.
- Elevated RTP801 in AD samples correlated with decreased XBP1 splicing; RTP801 silencing in 5xFAD mice restored XBP1 splicing and prevented aberrant tRNA accumulation and dendritic defects.
Conclusions:
- RTP801 impairs RNA processing, including XBP1 splicing and tRNA ligation, in vitro and in vivo.
- Dysfunctional RNA processing due to elevated RTP801 contributes to AD pathogenesis.
- Inhibiting RTP801 represents a promising therapeutic strategy for Alzheimer's disease.
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