TDP-43 Hexamutant (W→S) Monomers

TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed RNA/DNA-binding protein that plays a pivotal role in RNA processing, including RNA splicing, mRNA turnover, and microRNA biogenesis. Its pathological mislocalization from the nucleus to the cytoplasm, accompanied by aggregation and post-translational modifications, is a hallmark of several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer’s disease. These TDP-43 proteinopathies disrupt nucleocytoplasmic transport and mitochondrial function, contributing to neuronal dysfunction and death. Recent studies have also highlighted TDP-43’s involvement in DNA repair and chromatin remodeling, expanding its relevance in neurobiology beyond RNA processing. Notably, Pokrishevsky et al. (2024) demonstrated that when all six tryptophans are mutated to serines (trpless), this significantly reduces the protein’s ability to cross-seed SOD1 aggregation. Our TDP-43 hexamutant monomers has shown a reduced propensity to aggregate.

TDP-43, TDP43, TARDBP, TAR DNA-binding protein 43, Transactive response DNA-binding protein 43, ALS10, TDP43_N domain-containing protein, TADBP_HUMAN, TADBP_MOUSE, TADBP_PONAB, TADBP_XENTR, TADBP_CHICK, TBPH, dmTDP43, dtar, dTBPH, dTDP, dTDP-43, tbph, TDPH, CG10327, Dmel_CG10327

Chhangani, D., & Rincon-Limas, D. E. (2022) . TDP-35, a truncated fragment of TDP-43, induces dose-dependent toxicity and apoptosis in flies. Neural regeneration research, 17 (11), 2441–2442. https://doi.org/10.4103/1673-5374.338997 Meneses, A., Koga, S., O'Leary, J., Dickson, D. W., Bu, G., & Zhao, N. (2021) . TDP-43 pathology in Alzheimer’s disease. Molecular Neurodegeneration, 16 (84) . https://doi.org/10.1186/s13024-021-00503-x Nilaver, B. I., & Urbanski, H. F. (2023) . Mechanisms underlying TDP-43 pathology and neurodegeneration: An updated mini-review. Frontiers in Aging Neuroscience, 15: 1142617. https://doi.org/10.3389/fnagi.2023.1142617 Pokrishevsky, E., DuVal, M. G., McAlary, L., Louadi, S., Pozzi, S., Roman, A., Plotkin, S. S., Dijkstra, A., Julien, J. P., Allison, W. T., & Cashman, N. R. (2024) . Tryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1. The Journal of biological chemistry, 300 (5), 107207. https://doi.org/10.1016/j.jbc.2024.107207

SEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMRGVRLVEGILHAPDAGSGNLVYVVNYPKDNKRKMDETDASSAVKVKRAVQKTSDLIVLGLPSKTTEQDLKEYFSTFGEVLMVQVKKDLKTGHSKGFGFVRFTEYETQVKVMSQRHMIDGRSCDCKLPNSKQSQDEPLRSRKVFVGRCTEDMTEDELREFFSQYGDVMDVFIPKPFRAFAFVTFADDQIAQSLCGEDLIIKGISVHISNAEPKHNSNRQLERSGRFGGNPGGFGNQGGFGNSRGGGAGLGNNQGSNMGGGMNFGAFSINPAMMAAAQAALQSSSGMMGMLASQQNQSGPSGNNQNQGNMQREPNQAFGSGNNSYSGSNSGAAIGSGSASNAGSGSGFNGGFGSSMDSKSSGSGM