TAR DNA-binding protein 43 (TDP-43) modifier genes

TDP-43 modifier genes refer to a group of genetic factors that influence the pathological aggregation and neurotoxicity of TAR DNA-binding protein 43 (TDP-43), a hallmark of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) (Elden et al., 2010, Nature). TDP-43 is an essential RNA-binding protein that regulates splicing and transport; however, in disease states, it mislocalizes from the nucleus to the cytoplasm, forming toxic aggregates (Sreedharan et al., 2008, Science). Modifier genes like Ataxin-2 (ATXN2), Stathmin-2 (STMN2), and UNC13A have been identified as critical regulators of this process, either by enhancing TDP-43 toxicity or by being downstream targets whose function is lost upon TDP-43 depletion (Melamed et al., 2019, Nature Neuroscience; Brown et al., 2022, Nature). These genes are considered high-priority therapeutic targets because their manipulation can potentially rescue the loss-of-function or mitigate the gain-of-toxic-function associated with TDP-43 proteinopathy. Current drug development efforts focus on using antisense oligonucleotides (ASOs) to either knockdown toxic modifiers like ATXN2 or restore the correct splicing of genes like STMN2 that are disrupted by TDP-43 pathology (Klim et al., 2019, Nature Neuroscience). For instance, BIIB105 is an ASO in clinical trials designed to lower ATXN2 levels, which has been shown to reduce TDP-43 aggregation and extend survival in animal models. The identification of these modifiers has shifted the therapeutic landscape from targeting TDP-43 directly to modulating the broader genetic network that governs its stability and function.

Other names

TDP-43 genetic modifiersModifiers of TDP-43 toxicityTARDBP modifiers

Therapeutic modulation involves the use of antisense oligonucleotides to either reduce the expression of potentiation modifiers or restore the expression of genes whose splicing is disrupted by TDP-43 loss-of-function.