RNA therapy shows promise for addressing key driver of ALS
Experimental treatment targets TDP-43 protein clumping
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An experimental RNA-based therapy shows promise for ALS by preventing TDP-43 protein clumping.
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The therapy halted motor neuron loss in mouse models.
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Researchers hope to one day move the treatment to clinical testing.
An international team of scientists has developed an RNA-based experimental medicine that has the potential to reduce clumping of the TDP-43 protein, a key molecular feature of amyotrophic lateral sclerosis (ALS).
The researchers determined, in precise molecular detail, how the RNA-based therapy interacts with the TDP-43 protein and showed that the therapy led to beneficial effects in cell and animal models of ALS. The scientists are now embarking on work to bring this new therapy into clinical testing.
“The strength of our study is that we now have both the mechanistic and therapeutic framework for these short RNAs, all the way from their effects on pure proteins, to cell models and patient-derived neurons, and even mouse models,” James Shorter, PhD, co-author of the study and a professor at the University of Pennsylvania’s Perelman School of Medicine, said in a university news story.
The study, “Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration,” was published in Science.
Protein clumping
ALS is marked by the degeneration and death of motor neurons, the nerve cells that control movement. The causes of ALS aren’t fully understood, but abnormalities with the TDP-43 protein are a well-established molecular hallmark of the disease.
Normally, TDP-43 is located in the nucleus, the compartment that houses DNA, where it helps process RNA molecules — templates produced when genes are read and used to make the corresponding proteins.
But in ALS, TDP-43 tends to move out of the nucleus into the cytoplasm, the liquid part of the cell. Once in the cytoplasm, TDP-43 proteins are prone to clumping together, forming aggregates that are toxic to nerve cells.
“In [ALS], you’re really fighting against two things: this nuclear loss of TDP-43 function—disrupting RNA … processing—and a cytoplasmic gain of toxic function through protein aggregation,” Shorter said.
Shorter and colleagues previously found that a small RNA molecule, Clip34, can help prevent toxic TDP-43 clumping, but the molecular mechanisms remained unclear. They conducted a detailed set of experiments showing exactly how Clip34 binds to TDP-43.
They found that Clip34 sticks to the parts of the TDP-43 protein that normally bind RNA, known as the RNA-recognition motifs. This causes a change in the shape of the TDP-43 protein, destabilizing part of the protein called the prion-like domain. Prions are misfolded proteins that form toxic clumps, and as the name suggests, the prion-like domain plays key roles in TDP-43 clumping in ALS.
“We think that the way the short RNA binding affects the structure of that prion-like domain is important for keeping TDP-43 soluble [not clumped],” said Katie Copley, PhD, a former graduate student in Shorter’s lab and first author of the study.
Once they figured out exactly how Clip34 stabilizes TDP-43, the researchers ran a series of experiments testing other similar RNA molecules against various disease-related versions of the TDP-43 protein. Their goal was to find an RNA molecule with optimal impact on all versions of the abnormal TDP-43 protein, and they zeroed in on one called Malat1_start.
“We’re very excited about [Malat1_start] because it is more broadly effective against diverse TDP-43 variants than Clip34,” Copley said.
The team then tested Malat1_start in nerve cells derived from people with ALS and in a mouse model of the disease. Across models, the RNA-based therapy was able to stabilize TDP-43, so it stayed in the nucleus instead of moving to the cytoplasm and forming clumps.
“By getting the cytoplasmic TDP-43 back into the nucleus, we should be able to restore all of its functions,” Shorter said. “That’s the attractive feature of our strategy. As far as we know, nothing else has been shown to do this in a mouse model.”
And in the mouse model, Malat1_start treatment largely halted the loss of motor neurons — an effect Copley described as “pretty impressive.”
The researchers are conducting further tests with Malat1_start, aiming to identify optimal doses of the experimental therapy and test its effect in other mouse models, with the aim of eventually moving it into clinical testing.
“We’re really excited to advance [this therapeutic strategy] further,” Shorter said.
Alex Viale
Promising. Run fast with this please. Those of us with ALS now don't have years.
Graham Douglas
Heard about TDP43 in 2025 and it’s common in people with motor neuron disease. Whilst this sounds promising, it seems it might slow the progression, think better early diagnosis before the damage is done is key.