Abstract: TAR DNA-binding protein 43 (TDP-43) is an essential 414 amino acid protein that regulates multiple aspects of RNA biogenesis, processing, and transport.  It localizes primarily in the nucleus, but abnormal translocation and accumulation in the cytosol occur under pathological conditions (Tziortzouda et al., 2021). TDP-43 abnormalities are typical pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Mutations in the TDP-43-encoding gene TARDBP cause familial ALS, while wild-type TDP-43 is associated with almost all (~97%) of sporadic ALS cases and nearly half of frontotemporal lobar degeneration patients (~45%) (de Boer et al., 2020). Extensive research has identified post-translational modifications of TDP-43 such as phosphorylation, ubiquitination and truncation as major histopathological characteristics in TDP-43 proteinopathies. Substantial progress has occurred in studying protein aggregation involving phosphorylated and ubiquitinated TDP-43. However, as recently discussed by us, the relevance and pathological role of truncated TDP-43 forms are still poorly understood (Chhangani et al., 2021). Here we extend our discussion on truncation of TDP-43, present new experimental insights into the neurotoxic role of its cleaved TDP-35 fragment, and provide a perspective on new avenues of research in this field.