Exploring RNA and Exogenous Prions as Modulators of Protein Aggregation and Toxicity

Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), represent some of the most urgent global health challenges, affecting millions of people and imposing significant socio-economic burdens. These conditions are characterized by the accumulation of misfolded protein aggregates, such as amyloid-beta (AB), tau, and alpha-synuclein, which propagate toxic conformations across neurons. While genetic mutations contribute to some cases, the majority of neurodegenerative diseases are sporadic, suggesting a strong influence of environmental factors and lifestyle. However, the specific mechanisms by which external factors drive protein misfolding and neuronal damage remain poorly understood. Emerging evidence highlights the gut microbiota as a critical player in neurodegenerative processes. Alterations in microbiota composition have been consistently observed in patients with AD and PD, with certain microbial species correlating with disease severity. A striking example is Helicobacter pylori (H. pylori), a bacterium increasingly recognized for its ability to exacerbate AD progression. In our previous project, we identified H. pylori prion-like proteins capable of accelerating AB aggregation, inducing oxidative stress, and triggering neuronal damage, underscoring their pathogenic potential. RNA has also emerged as a pivotal modulator of protein aggregation, acting as both a stabilizer of functional biomolecular condensates and a promoter of toxic aggregation. Recent research demonstrates that RNA can influence the structure, aggregation, and toxicity of amyloid proteins, including Aβ and tau. However, its precise role in neurodegenerative diseases remains poorly defined, representing a critical knowledge gap this project aims to address. This project seeks to uncover the mechanisms by which microbial prion-like proteins and RNA modulate protein aggregation and toxicity, contributing to neurodegenerative disease progression. By integrating the study of RNA and microbial proteins, this project will shed light on environmental drivers of neurodegeneration, revealing novel molecular targets for therapeutic intervention. The findings could lead to innovative strategies for modulating the microbiome, developing RNA-based interventions, and designing personalized treatments for neurodegenerative diseases. Beyond expanding our scientific understanding, the research addresses a critical gap in current knowledge, with potential applications in microbiome-targeted therapies and RNA therapeutics. Overall, this project aligns with the global health challenge of tackling neurodegenerative diseases, contributing to the broader scientific effort to mitigate the socio-economic burden of these devastating conditions.