(1031-B) A combined TDP43-Tau cellular model for the understanding of LATE-NC Proteinopathy

Abstract: TDP-43 protein is known as the major disease protein in amyotrophic lateral sclerosis (ALS) and in the most common variant of frontotemporal lobar degeneration (FTLD). Recently, TDP-43 proteinopathy has been related with a newly recognized type of dementia, limbic-predominant agerelated TDP-43 encephalopathy (LATE-NC). Several studies have shown that almost 50% of patients with LATE-NC also present TDP-43 protein deposits in their brain cells. Although the true role of TDP-43 in LATE-NC and its relationship with pathological forms of Tau is currently unknown, in recent years it has been revealed that they may coexist in exacerbated forms of the disease. The development of a cellular assay aimed to study the behavior of the TDP43-TAR protein in combination with hyperphosphorylated Tau protein may allow us to elucidate new pathways of molecular signaling in LATE disease, as well as to screen compounds that may intercede in the pathological synergy between these two targets. Using this HCS assay in 96 well format, we performed the screening of a small synthetic chemical library of 1,200 compounds. The Z′ factor of the assay was over 0.5 demonstrating the robust performance of the assay. After the screening campaign, the positive compounds were chosen for further testing, based on the strength of the initial response and the lack of cytotoxicity.