The role of TDP-43 in ALS pathology

TAR DNA Binding Protein 43 kDa (TDP-43) aggregates are a pathological hallmark of almost all cases of amyotrophic lateral sclerosis (ALS), regardless of TDP-43 mutational status. Pamela Shaw, DBE, MBBS, MD, FRCP, FMedSci, FAAN, FANA, FAAAS, University of Sheffield, Sheffield, UK, explains how TDP-43 contributes to ALS pathology. Normally, TDP-43 resides in the nucleus, however it can shuttle between the nucleus and the cytoplasm to carry out diverse cell functions. Notably, TDP-43 is important for many different aspects of RNA processing, including the correct splicing of genes. Translocation of TDP-43 into the cytoplasm and cytoplasmic aggregation of TDP-43 lowers the nuclear level of TDP-43 and leads to a loss of function concerning TDP-43 regulation of RNA processing. Critically, pathogenic TDP-43 results in aberrant splicing and reduced protein levels of stathmin-2, which is important for axonal development and maintenance, thereby affecting the axonal health of motor neurons. This interview took place at the 18th Annual Congress on Controversies in Neurology (CONy 2024) in London, UK.
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