Problems with a protein known as TAR DNA-binding protein 43 (TDP-43) have long been associated with the neurodegenerative disorders Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). These neurological disorders have different effects on the brain and nerves, but they can both lead to serious declines in cognitive or physical abilities. Although TDP-43 builds up abnormally in both AD and ALS in the cytoplasm of cells and is reduced in the nucleus, scientists are still trying to understand exactly how this happens, and how it contributes to the pathology of neurological diseases.
Two new studies have now provided some insights into this process. This work has suggested that the depletion of TDP-43 from the nucleus of cells may impact a cellular process called alternative polyadenylation (APA), which has a critical role in gene expression and protein function.
"Our project emerged from a critical gap in understanding how TDP-43 dysfunction affects RNA processing in ALS and FTD. TDP-43 is a master editor of RNA in cells," co-first study author of one Nature Neuroscience report and Stanford University researcher Yi Zeng told Medical Xpress.
Zeng explained that in both ALS and frontotemporal dementia, TDP-43 exits the nucleus and accumulates in the cytoplasm, where toxic clumps form. Studies have indicated that this leads to editing problems in active genes; the mRNA transcripts of these genes are improperly spliced, and the resulting proteins carry unwanted regions. Genes such as STMN2 and UNC13A are affected.
Some previous work has showed that TDP-43 helps to find the stopping point of mRNA transcripts through polyadenylation.
"Think of it like deciding where to put the period at the end of a sentence—put it in the wrong place and you completely change the meaning," said Zeng. "Where an RNA ends determines its stability, localization, how much protein gets made, and even what kind of protein gets made, so different ending points can completely change a gene's output."
The STMN2 mRNA transcript, for example, ends too soon and also includes portions that it should not have, added Zeng. The team found disruptions in polyadenylation by searching datasets from patients, and then validated their findings in cells that were reprogrammed as neurons. They were able to reduce the levels of TDP-43 to mimic disease, and map the polyadenylation sites that were affected when TDP-43 was lost.
"Importantly, we validated our findings in patient samples, confirming these polyadenylation changes occur in actual patients, not just models," added Zeng.
In a second Nature Neuroscience study, researchers searched for instances of APA when TDP-43 was reduced in cells. This work provided some insights into how TDP-43 regulates APA, and also confirmed that the loss of TDP-43 negatively affects polydenylation in hundreds of genes.
“We now have a more complete picture of TDP-43 dysfunction: both splicing and polyadenylation defects affecting hundreds of genes critical for neuron survival. These polyadenylation changes could help detect TDP-43 pathology, track disease progression, and measure therapeutic response, addressing a key field need,” said Zeng.
Now the researchers want to find ways to reverse or stop the polyadnylation problems that are caused by the loss of TDP-43.
"The overarching goal is to use this more complete understanding of TDP-43 dysfunction to develop tools that help patients,” Zeng noted.
Sources: Medical Express, Yi Zeng et al Nature Neuroscience 2025, Sam Bryce-Smith et al Nature Neuroscience 2025