KEYWORDS
amyotrophic lateral sclerosis, ALS, TDP-43, TARDBP, randomized clinical trial, cytoplasmic aggregates, mislocalization, N-terminal domain (NTD) and nuclear localization signal (NLS)
INTRODUCTION
Functions of TDP-43
The transactive response DNA binding protein, TARDBP gene, encodes the TAR DNA-binding protein of 43 kDa (TDP-43), a ubiquitous nuclear protein that binds to both DNA and RNA, and is important in RNA processing, including transcriptional repression, regulation of non-coding RNA, miRNA biogenesis, alternative splicing, RNA stability, RNA trafficking, and auto-regulation of its own protein production \cite{Mejzini_2019}. The TARDBP protein is expressed early during development, and is involved in a wide range of RNA regulation processes, neurite outgrowth, and is ubiquitously expressed in a diversity of tissues. In addition, TDP-43 is important for genomic integrity maintenance as part of the DNA damage response pathway known as non-homologous end-joining (NHEJ). NHEJ is activated in response to DNA double-stranded breaks (DSB)\cite{Mitra_2019}.
Structure of TDP-43