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HEIndividual fellowship2023–2025

UNDERPIN · Untranslated regions of RNAs and protein networks in pathological phase separation: UNDERPIN

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-08-01 → 2025-07-31
EU contribution
€172,750
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

Untranslated regions of RNAs and protein networks in pathological phase separation: UNDERPIN

Neurodegenerative diseases—including Alzheimer's disease, Parkinson's disease, and multiple sclerosis—are among the most common age-related conditions. With populations ageing globally, the prevalence of neurodegenerative disorders is increasing, owing in part to the extensions in lifespan. Currently, there is no cure for any of these diseases. Increasing evidence indicates that RNA dysregulation is a shared driver of these disorders. In particular, mutations and aberrant expression of RNA-binding proteins (RBPs) frequently give rise to altered RNA–RBP interaction networks that contribute to neurodegenerative disease. RNA–RBP interaction are essential for the assembly of stress granules, transient cellular compartments, that act as storage hubs to safeguard RNAs and proteins during stress. Under chronic stress, when RBPs are mutated or dysregulated stress granule dynamics fail and can seed pathological aggregates. However, the causal links between RNA control, stress granule persistence, and RBP aggregation remain incompletely defined. UNDERPIN seeks to elucidate how mutations within RNA regulatory regions modulate the expression of RBPs, perturb their interaction networks, and ultimately affect stress granule formation. We combined computational and experimental approaches to assess the effects of single-nucleotide mutations in mRNAs encoding RBPs, thereby clarifying the mechanisms that underpin RBP regulatory networks.

Data: CORDIS, © European Union

Project objective

Aggregation of RNA binding proteins (RBPs) is a pathological hallmark of neurodegenerative pathologies such as Amyotrophic Lateral Sclerosis. The mechanism leading to RBP aggregation relies on the ability of these proteins to transition into membrane-less compartments such as the stress granules (SG) whose formation is normally regulated in physiological conditions. Yet, as RBPs are intrinsically prone to coalesce in large assemblies, their accumulation, when unregulated, can lead to cell toxicity. While the effects of amino acid mutations on RBP aggregation have been extensively investigated, a large amount of evidence indicates that nucleotide variants in untranslated regions (UTRs) can strongly impact RBP expression by altering the interactions with specific regulatory proteins. UTRs provide a platform where multiple RBPs bind to orchestrate post-transcriptional regulation. I envision that UTRs, by directing contacting specific protein networks are crucial in aggregate formation and that alteration of their interactomesdue to disease-linked mutationscould impact the propensity to form SG and other assemblies. The main objective of UNDERPIN is to reveal interactions in regulatory regions of RBPs and to understand their effects on phase separation in physiology and pathology. Firstly, I plan to investigate the effects of disease-linked mutations on UTRs of RNAs encoding RBPs by large-scale predictions of UTR-RBP interactors. Secondly, interactions between RBP and selected UTRs, with and without disease-linked mutations, will be revealed in human cells by RNA-protein interaction detection experimental method RaPID. Finally, the biological implications of UTR-mediated recruitment of RBPs will be deciphered providing molecular details on how UTRs and RBPs promote the formation of aggregates. Successful completion of this project will not only lead to new insights into RBP biology, but will also pave the way to understand early events of neurodegeneration.

Original text from CORDIS.

Participants

  • FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA · GenovaCoordinatorItaly

Links

Data: CORDIS, © European Union