RNA-binding protein that is involved in various steps of RNA biogenesis and processing. Preferentially binds, via its two RNA recognition motifs RRM1 and RRM2, to GU-repeats on RNA molecules predominantly localized within long introns and in the 3'UTR of mRNAs. In turn, regulates the splicing of many non-coding and protein-coding RNAs including proteins involved in neuronal survival, as well as mRNAs that encode proteins relevant for neurodegenerative diseases. Plays a role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts. Regulates also mRNA stability by recruiting CNOT7/CAF1 deadenylase on mRNA 3'UTR leading to poly(A) tail deadenylation and thus shortening. In response to oxidative insult, associates with stalled ribosomes localized to stress granules (SGs) and contributes to cell survival (By similarity). Participates also in the normal skeletal muscle formation and regeneration, forming cytoplasmic myo-granules and binding mRNAs that encode sarcomeric proteins (PubMed:30464263). Plays a role in the maintenance of the circadian clock periodicity via stabilization of the CRY1 and CRY2 proteins in a FBXL3-dependent manner (PubMed:27123980). Negatively regulates the expression of CDK6 (By similarity). Regulates the expression of HDAC6, ATG7 and VCP in a PPIA/CYPA-dependent manner (PubMed:25678563). Homodimer. Homooligomer (via its N-terminal domain) (By similarity). Interacts with BRDT (PubMed:22570411). Binds specifically to pyrimidine-rich motifs of TAR DNA and to single stranded TG repeated sequences. Binds to RNA, specifically to UG repeated sequences with a minimum of six contiguous repeats. Interacts with ATXN2; the interaction is RNA-dependent. Interacts with MATR3. Interacts with UBQLN2. Interacts with HNRNPA2B1 (By similarity). Interacts with ZNF106 (PubMed:28072389). Interacts with CNOT7/CAF1 (By similarity). Interacts with CRY2 (PubMed:27123980). Interacts with PPIA/CYPA; the interaction is dependent on RNA-binding activity of TARDBP and PPIase activity of PPIA/CYPA (PubMed:25678563). Acetylation of PPIA/CYPA at 'Lys-125' favors the interaction of TARDBP with PPIA/CYPA (By similarity). Continuously travels in and out of the nucleus. Localizes to stress granules in response to oxidative stress. A small subset localizes in mitochondria. The RRM domains can bind to both DNA and RNA. Hyperphosphorylated. Ubiquitinated. TARDBP depletion leads to atrophy of spinal motor neurons. Affects motor axon, neuromuscular junction and skeletal muscle.