**3.4 TDP-43 pathology**

TAR DNA-binding protein (TDP-43) protein has been identified as a regulator of gene expression and exon splicing with DNA and RNA binding capabilities. Hence, though TDP-43 is synthesized in the cytoplasm and resides in the nucleus of neurons and glia, under pathological conditions TDP-43 is accumulated in the cytoplasm in the form of ubiquitinated and hyperphosphorylated inclusions [82] (**Figure 1**). Pathological TDP-43 has been identified as the main disease-associated protein in ALS and FTLD. It has also been recognized as a secondary feature in many other neurodegenerative diseases, including Huntington disease, AD and PD [83]. Axonal damage results in an upregulation of TDP-43 expression, together with a redistribution of TDP-43 from the nuclear compartment to the cytoplasm [33, 84]. TBI induces TDP-43 abnormalities that can contribute to the neurological consequences of TBI, such as worse cell death, and cognitive deficits [85]. TDP-43 proteinopathy is also part of the acute or delayed pathological sequelae of repetitive mild, concussive TBI or CTE pathogenesis [86, 87]. The TDP-43 proteinopathy associated with CTE is similar to that found in FTLD with TDP-43 inclusions [87]. Intraneuronal accumulation of non-phosphorylated TDP-43 after a single TBI has also been reported [88]. Contrarily, related studies failed to demonstrate an association between single TBI and TDP-43 proteinopathy, only with repetitive TBI, indicating that just many insults reinforcing acute upregulation are sufficient to cause TDP-43 aggregation. Importantly, aggregates of phospho-TDP-43 were not increased long-term following TBI [88]. To the best of our knowledge, a clear functional role of altered TDP-43 expression levels after TBI has not been demonstrated, though this might disrupt signaling pathways involved in neuronal dysfunction, as some authors have suggested [89].
