A research team from the University of Barcelona’s Institute of Neuroscience (UBneuro) has led a study describing a new molecular mechanism that affects RNA processing and alters the process of protein synthesis in the brains of Alzheimer’s patients. The study, conducted on post-mortem samples from patients and in animal models of the disease, will boost the design of future therapies for the treatment of this dementia and other neurological disorders.
Cristina Malagelada, who led the study, and Genís Campoy-Campos, the first author, published the article in Nucleic acid research. Malagelada is a professor at the Faculty of Medicine and Health Sciences of the UB and the UBneuro and, together with Campoy-Campos, is a member of the Center for Biomedical Research Network on Neurodegenerative Diseases (CIBERNED).
A new function for the RTP801 protein
Alzheimer’s disease is the most common form of dementia and causes a gradual decline in cognitive, memory and language skills, as well as emotional and psychiatric disorders. It is characterized by the accumulation of β-amyloid plaques outside the neurons and hyperphosphorylated tau protein inside the neurons, which alter brain function and cause cell death.
Now this study reveals a previously unknown role for the RTP801 protein, a stress response factor that is abundant in patients with neurodegenerative diseases such as Alzheimer’s disease. According to the findings, this protein can alter the molecular mechanisms that support the survival of neurons by affecting the translation of RNA into proteins.
Malagelada says that “until now we knew that the RTP801 protein, found in hippocampal neurons, was involved in the pathology of Alzheimer’s disease, as we published in a previous paper (Cell death and disease2021). At that time, we found that levels of this protein were significantly elevated in both mouse models of Alzheimer’s disease and in post-mortem samples from patients, and these values correlated with disease progression.”
“At a mechanistic level, we observed that reducing RTP801 expression prevented cognitive deficits and inflammation, mainly by reducing the activation of the hippocampal inflammasome, that is, the machinery that processes cytokines in inflammatory responses and drives gliosis (reactivation and proliferation of glial cells),” the expert continues.
Why is this mechanism crucial for neuronal health?
The study describes how the RTP801 factor negatively regulates the activity of the tRNA ligase complex (tRNA-LC), which is crucial for the processing of RNA molecules. In the context of Alzheimer’s disease, higher levels of RTP801 may inhibit this complex and cause problems in RNA splicing and subsequent production of relevant proteins, such as brain-derived neurotrophic factor (BDNF), causing cognitive problems in a mouse model of Alzheimer’s disease are exacerbated.
Campoy-Campos notes that “in this study we found that high levels of RTP801 interfere with the tRNA ligase complex, which is responsible for RNA processing, particularly during the exon ligation process, once the introns have been spliced. This The process takes place both in the messenger RNA – which carries the information to build the protein – and in the transfer RNAs, which carry the amino acids to translate it.” The researcher emphasizes that “this process is essential for the correct synthesis of proteins in the ribosome, the cell organelles where the translation of RNA into proteins takes place.”
Interestingly, this interaction between RTP801 and the tRNA ligase complex also affects the RNA binding of a transcription factor called XBP1s. This factor helps cells cope with stress in the endoplasmic reticulum – an organ formed by a series of cisternae and membranous cavities in the cell cytoplasm – and promotes the expression of BDNF, a neurotrophin crucial for synaptic transmission, memory and neuronal survival.
Genís Campoy-Campos, first author
Altered RNA processing – a consequence of high levels of RTP801 – is highly damaging to neurons, disrupting their ability to synthesize proteins and respond to stress. As Malagelada notes, this altered RNA processing adds a new toxic component to the known evolution of Alzheimer’s disease. “We now bring up the toxicity of unbound RNAs and its implications as a novel neurodegenerative mechanism in Alzheimer’s disease,” she says.
Encouraging future therapies for the treatment of neurodegenerative diseases
The discovery of novel functions of the RTP801 protein could open future therapeutic options to address the treatment of neurodegenerative pathologies and maintain brain function and neuronal health. In this sense, Malagelada points out that “if we can design inhibitors of the RTP801 protein – which we are currently working on – or preserve the activity of the tRNA ligase complex, we can specifically block the most toxic functions of this factor and essential functions can keep. neuronal processes”.
The researchers conclude that “this offers a new range of innovative therapeutic options in the context of these neurological disorders”.
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Magazine reference:
Campoy-Campos, et al. (2024). RTP801 interacts with the tRNA ligase complex and disrupts its RNA ligase activity in Alzheimer’s disease. Nucleic acid research. doi.org/10.1093/nar/gkae776.