TAR DNA-binding protein 43 messenger RNA (TDP-43 mRNA)

TAR DNA-binding protein 43 (TDP-43) messenger RNA is the transcript of the TARDBP gene, which encodes a protein essential for RNA metabolism, including splicing, transport, and stability (UniProt Q13148). In healthy cells, TDP-43 protein levels are tightly controlled through an autoregulatory feedback loop where the protein binds to its own mRNA 3' untranslated region (UTR) to trigger degradation (Polymenidou et al., 2011). Pathologically, TDP-43 is the hallmark protein found in aggregates in nearly all cases of Amyotrophic Lateral Sclerosis (ALS) and about half of Frontotemporal Dementia (FTD) cases (Neumann et al., 2006). These "TDP-43 proteinopathies" involve the loss of nuclear TDP-43 and the accumulation of toxic cytoplasmic inclusions. Therapeutic strategies targeting the mRNA, such as antisense oligonucleotides (ASOs), aim to reduce the production of TDP-43 to mitigate gain-of-toxicity effects. One such candidate, BIIB105, is an investigational ASO designed to lower TDP-43 protein levels by promoting the degradation of its mRNA (NCT04408638). A significant challenge in targeting this mRNA is the narrow therapeutic window, as TDP-43 is vital for the survival of neurons and other cell types, and excessive knockdown can lead to neurodegeneration.

Other names

TARDBP mRNATAR DNA-binding protein 43 transcriptTDP-43 transcript

Antisense oligonucleotide-mediated degradation of mRNA via RNase H recruitment