A Novel Regulator of RNA Processing in Alzheimer's Disease

A research team from the University of Barcelona's Institute of Neurosciences described a novel molecular mechanism that modifies protein synthesis and impacts RNA processing in Alzheimer's patients' brains.

The research, conducted on animal models of the disease and post-mortem patient samples, will improve the development of future treatments for dementia and other neurological conditions.

Cristina Malagelada, who led the study, and Genís Campoy-Campos, the first author, have published their findings in Nucleic Acids Research. Malagelada is a professor at the Faculty of Medicine and Health Sciences and UBneuro at the University of Barcelona (UB). Both she and Campoy-Campos are members of the Centre for Biomedical Research Network on Neurodegenerative Diseases (CIBERNED).

A New Function for the RTP801 Protein

The most prevalent kind of dementia, Alzheimer's disease, results in emotional and psychological problems along with a progressive deterioration in language, memory, and cognitive abilities.

It is typified by the buildup of tau protein that is hyperphosphorylated inside neurons and β-amyloid plaques outside neurons, which change brain function and result in cell death.

Until now, we knew that the RTP801 protein, which is found in hippocampal neurons, was involved in the pathology of Alzheimer’s, as we published in a previous article (Cell Death and Disease, 2021). Back then, we discovered that levels of this protein were significantly elevated in both mouse models of Alzheimer’s and in post-mortem samples from patients, and these values correlated with disease progression.”

Cristina Malagelada, Professor, University of Barcelona

“On a mechanistic level, we observed that reducing RTP801 expression prevented cognitive deficits and inflammation, especially by mitigating the activation of the hippocampal inflammasome, i.e. the machinery that processes cytokines in inflammatory responses and drives gliosis (reactivation and proliferation of glial cells),” Malagelada continued.

Why is this Mechanism Crucial for Neuronal Health?

The study explains how the tRNA ligase complex (tRNA-LC), which is essential for digesting RNA molecules, is negatively regulated by the RTP801 factor. In a mouse model of Alzheimer's disease, elevated RTP801 levels can exacerbate cognitive issues by inhibiting this complex and impairing RNA splicing and the consequent synthesis of pertinent proteins, including brain-derived neurotrophic factor (BDNF).

In this study, we have found that high levels of RTP801 interfere with the tRNA ligase complex, which is responsible for RNA processing, specifically in the process of ligation of its exons, once the introns have been cleaved. This process takes place both in the messenger RNA which contains the information to build the protein and in the transfer RNAs, which carry the amino acids to translate it.”

Genís Campoy-Campos, Study First Author, University of Barcelona

The researcher stresses that “this process is vital for the correct synthesis of proteins at 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 set 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, Study First Author, University of Barcelona

High levels of RTP801 cause altered RNA processing, which is extremely harmful to neurons and impairs their capacity to respond to stress and manufacture proteins. Malagelada notes that this altered RNA processing contributes a new harmful element to the previously understood development of Alzheimer's disease.

“We now bring to the table the toxicity of unbound RNAs and its consequences as a new neurodegenerative mechanism in Alzheimer’s,” she said.

Boosting Future Therapies to Treat Neurodegenerative Diseases

The identification of novel roles for the RTP801 protein may lead to new therapeutic approaches for the management of neurodegenerative diseases and the maintenance of neuronal health and brain function.

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 could specifically block the most toxic functions of this factor and preserve essential neuronal processes.”

The researchers conclude that “this offers a new range of innovative therapeutic options in the context of these neurological disorders.”