TAR DNA-binding protein 43 (TDP-43) modifier gene mRNA (TDP-43 modifier mRNA)

TAR DNA-binding protein 43 (TDP-43) is an essential RNA-binding protein that regulates the splicing, transport, and stability of thousands of RNA transcripts (Elden et al., 2010). In neurodegenerative conditions like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), TDP-43 undergoes pathological mislocalization and aggregation, leading to both toxic gain-of-function and loss of essential nuclear functions (Klim et al., 2019). TDP-43-related modifier genes are a class of genetic targets that can alter the progression of this pathology or compensate for the loss of TDP-43-mediated RNA regulation (Elden et al., 2010). Notable modifiers include Ataxin-2 (ATXN2), which acts as a potent enhancer of TDP-43 toxicity, and Stathmin-2 (STMN2), an essential microtubule-regulator whose expression is lost due to cryptic splicing in the absence of nuclear TDP-43 (Klim et al., 2019; Brown et al., 2022). Therapeutic strategies targeting these modifiers often employ antisense oligonucleotides (ASOs) to either knockdown toxic proteins or restore the expression of functional mRNA transcripts (Biogen, 2023; QurAlis, 2023). For instance, BIIB105 is an ASO designed to reduce ATXN2 levels, while other experimental therapies aim to prevent the cryptic splicing of STMN2 or UNC13A (Biogen, 2023; QurAlis, 2023). Because this specific entry does not identify a single gene, it encompasses the broad landscape of genetic modifiers currently being investigated to treat TDP-43 proteinopathies. Monitoring these modifiers, particularly through the detection of cryptic splice variants in biofluids, serves as a promising biomarker strategy for patient stratification and target engagement (Brown et al., 2022).

Other names

TDP-43 genetic modifiersTDP-43 toxicity modifiersTDP-43 downstream targetsTDP-43-regulated mRNA

Antisense oligonucleotide (ASO) mediated modulation of mRNA levels or splicing patterns to mitigate TDP-43-induced neurotoxicity.