Multimodal bioinformatic analyses of the neurodegenerative disease-associated gene reveal its diverse roles.

Background: Loss of tectonin β-propeller repeat-containing 2 () function has been implicated in an array of neurodegenerative disorders, yet its physiological function remains largely unknown. Understanding function is essential for developing much needed precision therapeutics for TECPR2-related diseases.

Methods: We leveraged considerable amounts of functional data to obtain a comprehensive perspective of the role of in health and disease. We integrated expression patterns, population variation, phylogenetic profiling, protein-protein interactions and regulatory network data for a minimally biased multimodal functional analysis. Genes and proteins linked to via multiple lines of evidence were subject to functional enrichment analyses to identify molecular mechanisms involving TECPR2.

Results: TECPR2 was found to be part of a tight neurodevelopmental gene expression programme that includes , , and , all implicated in neurological diseases. Functional enrichment analyses of -related genes converged on a role in late autophagy and ribosomal processes. Large-scale population variation data demonstrated that this role is non-redundant.

Conclusions: TECPR2 might serve as an indicator for the energy balance between protein synthesis and autophagy, and a marker for diseases associated with their imbalance, such as Alzheimer's disease and Huntington's disease. Specifically, we speculate that TECPR2 plays an important role as a proteostasis regulator during synaptogenesis, highlighting its importance in developing neurons. By advancing our understanding of TECPR2 function, this work provides an essential stepping stone towards the development of precision diagnostics and targeted treatment options for TECPR2-related disorders.