TDP-43 is also involved in mediating the transcription regulation of human immune deficiency virus (HIV). TDP-43 has been identified as the major ubiquinated component of cytoplasmic inclusions in frontotemporal lobe degeneration subtype FTLD-U and amyotrophic lateral sclerosis (ALS). Pathological TDP-43 forms abnormal inclusions in neuronal perikarya and neurites, indicating that redistribution of TDP-43 to the cytoplasm is a pathogenic mechanism. Several pathogenic TDP43 mutations have been identified in familial ALS, causing aberrant cleavage of TDP-43 to C-terminal fragments, and predisposing nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates. Abnormal phosphorylation of TDP-43 at Ser409/410 has also been observed in frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD-U and ALS) suggesting a toxic gain of function leading to apoptosis.
