Exploring Proteogenomic Approaches to Unravel the Mechanisms of Mis-Folded Protein Accumulation in Tauopathies (R01 Clinical Trial Not Allowed)

Notice of Funding Opportunity Description Background The accumulation of misprocessed and aberrant proteins is a defining characteristic of various neurodegenerative conditions, such as AD and frontotemporal lobar degeneration (FTLD). These atypical proteins may arise from various factors, such as somatic mutations, environmental changes, genomic instability, irregular RNA processing, and proteolytic cleavages, as well as incorrect folding and post-translational modifications. For instance, many recent proteome and transcriptome profiling of AD brains reveals RNA splicing dysfunction and abnormal accumulation of U1 small nuclear ribonucleoprotein (snRNP) and transactive response DNA-binding protein 43 (TDP-43). In AD, U1-70K and its N-terminal 40-KDa fragment (N40K) is one of the most abundant proteins in the insoluble fraction of cell lysates. TDP-43 is an RNA-binding protein. In AD, TDP-43 pathology is observed in approximately 25-50% of cases, particularly in cases with co-morbidities such as Lewy body dementia or hippocampal sclerosis. However, the relationship between U1snRNP/TDP-43 and AD pathology is complex and not fully understood. The disruption of RNA processing is thought to be one possible mechanism to cause the accumulation of misprocessed proteins, which can lead to altered expression of genes involved in AD pathology, including amyloid precursor protein (APP), tau, and synaptic proteins. Understanding the mechanisms underlying the dysregulation of misprocessed proteins in neurodegenerative diseases will be important for developing effective therapies. Approaches that target the production or aggregation of misprocessed proteins, or that promote their clearance or degradation, may be effective in preventing or slowing disease progression. Purpose This NOFO invites innovative research proposals to explore the accumulation of misprocessed proteins in Tauopathies within specific brain regions and cell types. This NOFO encourages collaborative efforts to create advanced single-cell or single-cell type proteogenomic platforms. These platforms aim to shed light on dynamic changes in protein-misfolding responses in neuronal proteomes and their potential biological consequences during aging and the development of AD/ADRD. Research Objectives This NOFO aims to provide a proof-of-principal for a novel strategy to identify misprocessed and aberrant proteins in Tau diseases using the proteogenomic approach. Proteogenomics is an integrated approach that combines proteomics and genomics data. In proteogenomics, genomic and transcriptomic experiments are more closely integrated to identify potential protein coding and non-coding regions in the genome. These regions are then validated using mass spectrometry-based proteomics. Proteogenomics has emerged as a powerful tool for investigating the role of protein homeostasis in AD pathogenesis, especially in the context of mis-translated and mis-repaired proteins. However, relying solely on misprocessed protein levels to draw conclusions about biological processes is unlikely to be reliable. Therefore, an intermediate layer of functional validation is essential to transform proteogeomic data into meaningful biological information. As a result, the objective of this NOFO is not only to confirm changes in protein abundance using other methods, but also to assess the biological effects of those changes in some model systems, especially in the area of tauopathies, to ensure high interlaboratory reproducibility. Using the proteogenomics approach, this NOFO aims to accomplish the following: Create a comprehensive database of misprocessed and aberrant proteins in selected mouse models of human Tau diseases. Cross-validate the presence of misprocessed and aberrant proteins in human AD/ADRD brains. Identify new molecular pathways and novel misprocessed protein-protein interaction networks that are not currently in most datasets. Define novel mechanisms through which misprocessed and aberrant proteins influence the onset and progression of neurodegeneration in tauopathies. Identify disease specific therapeutic targets in neurodegenerative diseases. It is expected that applications responding to this initiative will use the latest cell-type-specific labeling and proteogenomic techniques with suitable model systems to understand the etiology of tauopathies in aging and AD.