New strategy prevents toxic protein clumps that drive ALS: Study
Targeted treatment preserves normal function, extends survival in animal models
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- ALS is linked to toxic TDP-43 protein clumps. A new strategy targets a specific protein region.
- A small molecule, XL20, prevents clumping, reducing nerve damage in human cells.
- XL20 extended survival and improved motor function in ALS mouse models, showing promise.
Targeting a specific part of the TDP-43 protein can prevent toxic protein clumping that drives amyotrophic lateral sclerosis (ALS) without disrupting the protein’s normal function, a new study shows.
“Current [U.S.-approved] treatments for ALS provide only modest benefits. There is an urgent need for a real breakthrough,” Xinglong Wang, PhD, the study’s senior author and a professor at the University of Arizona’s R. Ken Coit College of Pharmacy, said in a university news story. “We asked a simple question that had never been tested: Is there one specific part of TDP-43 that’s causing the harm, something a drug could switch off without disturbing the rest?”
The researchers have already identified a small molecule that is able to target this specific part of the TDP-43 protein, and they showed that this molecule extended survival and decreased nerve damage in a mouse model of ALS.
“These findings expand our understanding of TDP-43 neurotoxicity and provide a strong foundation for the development of therapeutic strategies targeting TDP-43-associated neurodegeneration,” researchers wrote.
The study, “Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice,” was published in Nature Aging.
Dysregulation of TDP-43 protein a molecular hallmark of ALS
ALS is marked by the death of motor neurons, the nerve cells that control movement. The causes of ALS are not fully understood, but a molecular hallmark of the disease is dysregulation of the TDP-43 protein.
This protein is normally present in nerve cells and helps regulate gene activity, but in ALS, TDP-43 forms toxic clumps that damage nerve cells and contribute to disease progression. A minority of ALS patients have mutations in TARDBP, the gene that encodes TDP-43, but this protein also forms toxic clumps in ALS patients who don’t have such mutations.
Preventing TDP-43 from forming toxic clumps is widely seen as a promising strategy for developing new ALS treatments. But it’s been difficult for scientists to find a way to prevent these clumps without also disrupting the protein’s normal functions.
A decade-long effort
In this study, Wang and colleagues looked in detail at the structure of the TDP-43 protein, hoping to find specific regions that could be targeted to prevent clumping without interfering with the protein’s function.
The team zeroed in on a specific part of the TDP-43 protein that is critical for regulating the protein’s functional assembly and is evolutionarily conserved across species. A lot of ALS-associated TARDBP gene mutations specifically affect this conserved region (CR) of the TDP-43 protein.
The researchers found that increasing the production of the full TDP-43 protein in lab-grown mouse nerve cells triggered protein clumping and nerve damage akin to what’s seen in ALS. But when the researchers promoted the production of a version of the TDP-43 protein where the CR was deleted, the protein didn’t clump or cause damage.
“These results collectively suggest that CR is critical in mediating neuronal toxicity induced by [high levels of] TDP-43,” the researchers wrote.
In a wide range of further experiments, the team showed that deleting the CR from TDP-43 doesn’t disturb the protein’s natural function. According to Wang, most of this decade-long study was dedicated to tests to ensure that deleting the CR wouldn’t cause unexpected problems.
“By targeting a domain essential for neurotoxicity without disrupting key [protein] functions, we show that TDP-43-associated neurodegeneration may be effectively suppressed,” the scientists wrote.
After confirming that such functions wouldn’t be disrupted, the researchers set out to find small molecules that could target the CR region in TDP-43. They identified one such small molecule, called XL20, that is able to cross into the brain and specifically target the CR.
Perhaps one of the most promising aspects of this study is the identification of a potent small molecule capable of binding TDP-43 to suppress its neurotoxicity without impacting [the protein’s main localization and] function.
In lab-grown human motor neurons, treatment with XL20 reduced nerve damage driven by TDP-43 clumping. And in mice with a TARDBP gene mutation (widely used as a model of ALS), XL20 treatment led to improved motor function and modest extensions in lifespan. The researchers also confirmed that XL20 treatment didn’t disrupt TDP-43’s normal activities.
“Perhaps one of the most promising aspects of this study is the identification of a potent small molecule capable of binding TDP-43 to suppress its neurotoxicity without impacting [the protein’s main localization and] function,” the researchers wrote.
The team said these findings position XL20 as a promising potential treatment for ALS. And because TDP-43 has also been implicated in other neurological disorders, the findings may have implications for other diseases.
“If future studies show this approach works in those diseases as well, it could eventually benefit a much larger patient population,” Wang said.
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