Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>TDP‐43 is a highly conserved protein localized to the nucleus. Under pathological conditions, it forms fibrillar aggregates, characteristic of Amyotrophic Lateral Sclerosis (ALS) progression. The exact mechanism of TDP‐43 aggregation and formation into a pathological state has yet to be elucidated, but is an important therapeutic target to consider.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In vitro full‐length phosphorylated TDP‐43 (pS410)protein was agitated and aged, with and without the presence of TDP‐43 specific antibodies. Immunoblotting was used to confirm the binding of antibodies to TDP‐43. Aggregation was monitored using spectroscopic methods, Thioflavin T (ThT), and turbidity. Transmission electron microscopy (TEM) visualized the formation and structure of phospho‐TDP‐43 aggregates.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The agitation and extensive aging (days) were required to induce aggregation of insoluble phospho‐TDP‐43 aggregates and formation of ThT positive fibrils. When exposed to an antibody specific to the RRM2‐CTD domain on TDP‐43, aggregation was inhibited in a concentration‐dependent manner and fibril formation was reduced.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Inhibition of TDP‐43 aggregation and fibril formation using antibodies demonstrates the potential for epitope‐specific treatment of TDP‐43 proteinopathies.</jats:p><jats:p>1) Esposto, J., & Martic‐Milne, S. (2021). Phosphorylated TAR DNA‐binding protein‐43: aggregation and antibody‐based inhibition. Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease, 1867, https://doi.org/10.1016/j.bbadis.2021.166234.</jats:p></jats:sec>