Small molecule slows nerve damage in ALS mice
ALS kills nerve cells fast, and no treatment stops the process. A small molecule that blocks a specific toxic region of a misfolded protein has now slowed that damage in mice and extended their survival.
ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative disease characterised by the loss of motor neurons. A key feature is the accumulation of a misfolded form of the protein TDP-43, which normally helps process genetic information inside cells. In ALS, TDP-43 clumps together and loses its normal function. The researchers identified a specific toxic region within TDP-43’s low-complexity domain and developed a small molecule to target it. The study was published in Nature Aging.
A molecule that crosses the blood-brain barrier
The compound is brain-penetrant, meaning it can cross the blood-brain barrier. That is a critical property, as many candidate drugs fail at this hurdle. In mouse models of ALS, the molecule improved mitochondrial function (the energy-producing machinery of cells), reduced neurodegeneration, and extended survival.
Mitochondrial dysfunction is a known feature of ALS. When TDP-43 accumulates, the energy machinery of nerve cells becomes impaired, accelerating cell death. The molecule appears to interrupt that link by neutralising the toxic region of TDP-43.
Still a long road ahead
The results are currently limited to animal models. Whether the approach works in humans and whether the molecule is safe long-term remains unknown. ALS has a long history of promising animal findings that did not translate to the clinic.
From a broader longevity perspective, TDP-43 aggregation is also found in other age-related neurodegenerative conditions, including frontotemporal dementia. A molecule that neutralises the toxic domain of TDP-43 could in principle have wider applicability.
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