Unraveling the Role of RTP801 in Alzheimer’s Disease: A New Mechanism of RNA Dysregulation and Its Therapeutic Potential
A groundbreaking study published in Nucleic Acids Research has identified a critical mechanism linking the protein RTP801 to Alzheimer’s disease (AD). Led by Cristina Malagelada, PhD and her team at the Institute of Neurosciences of the University of Barcelona, the research uncovers how elevated levels of RTP801 disrupt essential RNA processes in the hippocampus, a brain region central to memory.
Alzheimer’s disease (AD) is the most common type of dementia, leading to a gradual decline in thinking skills, memory, and language abilities, along with emotional and psychiatric issues. It is characterized by the buildup of amyloid-β plaques outside neurons and tau tangles inside neurons, which disrupt brain function and cause cell death. RTP801, a protein that increases in response to stress and is found at higher levels in the brains of AD patients, may play a role in the disease by negatively affecting important cellular processes that help with survival and translation of RNA into proteins.
“Until now, we knew that RTP801, found in neurons of the hippocampus, was involved in Alzheimer’s pathology, as we published in 2021,” Dr. Malagelada explains. “Back then, we discovered that levels of this protein were significantly elevated in both Alzheimer’s mouse models and postmortem patient samples, correlating with disease progression. At a mechanistic level, we observed that reducing RTP801 expression prevented cognitive deficits and neuroinflammation, especially by mitigating the activation of the hippocampal inflammasome—the machinery that processes cytokines and drives gliosis.”
Why this Mechanism is Crucial for Neuronal Health
The study identifies RTP801 as a new protein that negatively regulates the activity of the tRNA ligase complex (tRNA-LC), which is important for processing RNA molecules. In the context of Alzheimer’s disease (AD), higher levels of RTP801 can inhibit this complex, leading to problems in RNA splicing and the production of important proteins like BDNF, which may worsen cognitive issues in a mouse model of AD. The researchers suggest that targeting RTP801 could be a potential strategy for developing therapies for Alzheimer’s disease. The latest findings reveal a previously unknown role for RTP801. “In this study, we found that high levels of RTP801 interfere with the tRNA ligase complex, which is responsible for RNA processing, specifically the ligation of tRNA exons,” says Dr. Malagelada. “This process is vital for proper protein synthesis at the ribosome. Interestingly, this interaction between RTP801 and the tRNA ligase complex also affects the splicing of a transcription factor called XBP1s, which helps cells cope with endoplasmic reticulum stress and promotes the expression of BDNF, a neurotrophin crucial for synaptic transmission, memory, and neuronal survival.”
This RNA processing defect, driven by elevated RTP801, is highly detrimental to neurons, impairing their ability to synthesize proteins and respond to stress. According to Dr. Malagelada, this RNA misprocessing adds a new layer to the toxic cascade in Alzheimer’s: “We are now putting on the table the toxicity of unligated RNAs and their consequences as a new neurodegenerative mechanism in Alzheimer’s”.
This discovery has profound implications for neuronal health. The interference caused by RTP801 leads to the accumulation of unspliced RNAs, which further exacerbates neurodegenerative processes in Alzheimer’s.
Potential Clinical Applications
In terms of therapeutic potential, this discovery opens exciting new possibilities. “In the long run, if we can design inhibitors of the RTP801 protein—which we are currently working on—or preserve the tRNA ligase complex’s activity, we could specifically block the most toxic functions while preserving essential neuronal processes,” Dr. Malagelada explains. “This offers a fascinating new range of therapeutic options in the context of dementia.”
By targeting RTP801 or mitigating the effects of unspliced RNAs, future treatments could prevent the progression of Alzheimer’s and potentially other neurodegenerative diseases, preserving brain function and quality of life. Therefore, preventing RTP801 levels from rising, could stop this defective RNA processing and, in turn, prevent cognitive deficits and neuroinflammation
Reference article:
Campoy-Campos, Genís; Solana-Balaguer, Julia et al. “RTP801 interacts with the tRNA ligase complex and dysregulates its RNA ligase activity in Alzheimer’s disease”. Nucleic Acids Research, September 2024. DOI: 10.1093/nar/gkae776
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