Fig. 3

Pathogenesis of TARDBP gene mutations. TDP-43 plays a crucial role in RNA/DNA binding and RNA metabolism, and its misfolding leads to the formation of toxic inclusions. The mislocalization and aggregation of TDP-43 trigger DNA damage responses and impair DNA repair mechanisms. Stress granules enriched in PAR bind to key proteins such as TDP-43 and FUS, resulting in abnormal localization and aggregation. Additionally, rTauO affects the localization and aggregation of TDP-43, promoting its translocation from the nucleus to the cytoplasm. TDP-43 mutations disrupt the mRNA splicing regulatory function of UNC13A, causing the inclusion of cryptic exons during RNA splicing and the production of abnormal proteins. In the absence of TDP-43 or in the presence of its mutations, hnRNP L acts as a disease modifier by binding to UNC13A RNA and inhibiting cryptic exon inclusion. Mislocalization of hnRNPs further contributes to neurodegeneration. Furthermore, the loss of TDP-43’s protective function over STMN2 pre-mRNA results in cryptic splicing and polyadenylation, leading to reduced STMN2 expression and impairing the axonal regeneration capacity of motor neurons. Figure created with BioRender.com