Researchers identify a new molecular mechanism that could help design future therapies to treat Alzheimer’s disease

A research team at the Institute of Neurosciences of the University of Barcelona (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, which has been carried out in post-mortem samples of patients and in animal models of the disease, will boost the design of future therapies to address the treatment of this dementia and other neurological disorders.

Cristina Malagelada, who led the study, and Genís Campoy-Campos, its first author, have published the paper in Nucleic Acids Research. Malagelada is a professor at the UB’s Faculty of Medicine and Health Sciences and the UBneuro and, together with Campoy-Campos, are members of the Centre for Biomedical Research Network on Neurodegenerative Diseases (CIBERNED).

A new function for the RTP801 protein

Alzheimer’s disease is the most common type of dementia and causes a gradual decline in cognition, memory and language skills, as well as emotional and psychiatric disorders. It is characterized by the accumulation of β-amyloid plaques outside neurons and hyperphosphorylated tau protein inside 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 neuronal survival by affecting the translation of RNA into proteins.

Malagelada says that “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”.

“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)”, continues the expert.

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 critical for processing RNA molecules. In the context of Alzheimer’s disease, higher levels of RTP801 can inhibit this complex and cause problems in RNA splicing and subsequent production of relevant proteins, such as brain-derived neurotrophic factor (BDNF), exacerbating cognitive problems in a mouse model of Alzheimer’s disease.

Campoy-Campos notes that “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”. 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”, Campoy-Campos adds.

Altered RNA processing — a consequence of high levels of RTP801 — is highly detrimental to neurons, disrupting their ability to synthesize proteins and respond to stress. As Malagelada points out, this altered RNA processing adds a new toxic component to the hitherto known evolution 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 says.

Boosting future therapies to treat neurodegenerative diseases

The discovery of new functions of the RTP801 protein could open up future therapeutic options to address the treatment of neurodegenerative pathologies and preserve 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 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”.