Abstract: Transactive response DNA binding protein of 43 kDa (TDP-43) is a ubiquitously expressed RNA/ DNA binding protein crucial for coding and noncoding RNA metabolism including transcription, splicing, transport, translation, and turnover. TDP-43 shuttles between the nucleus and cytoplasm, but is predominantly localized in the nucleus. Neurodegenerative diseases (NDs) may be accompanied by nuclear loss and possible cytoplasmic accumulation and aggregation of TDP-43 in vulnerable neurons and beyond. This neuropathology is the hallmark of most individuals suffering from amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) with TDP-43- immunoreactive pathology (FTD-TDP), limbicpredominant age–related TDP-43 encephalopathy (LATE) and Perry syndrome, but also coexists with the primary pathology in subsets of patients suffering from other NDs, such as Alzheimer’s disease, Lewy body dementias, or Huntington’s disease. Variants in the gene encoding TDP-43 (TARDBP) are the cause of ALS and/or FTD in some rare cases substantiating the importance of this protein in aging neurons. It is still controversial if loss of nuclear, or increased cytoplasmic and/or aggregating TDP-43 is more harmful to neurons (Nag and Schneider, 2023). Recently, the role of nuclear TDP-43 in repressing the inclusion of intronic sequences, named cryptic exons (CEs), into mature mRNAs gained much attention.