TDP-43 is one of a small number of proteins in the brain that can misfold or otherwise become altered in ways that allow toxic aggregates to form, or even encourage other molecules of the same protein to become dysfunctional in the same way. TDP-43 aggregation in later life is a relatively recent discovery, and has a neurodegenerative condition newly named for it, limbic-predominant age-related TDP-43 encephalopathy (LATE). It has also been found that TDP-43 is likely important in amyotrophic lateral sclerosis (ALS), and thus progress on that front seems likely to help with other forms of TDP-43 pathology. Here, researchers report a promising discovery in the biochemistry of TDP-43 aggregation in the context of ALS.
Amyotrophic lateral sclerosis (ALS) is a lethal adult-onset motor neuron disease, characterized by disruption of neuromuscular junctions (NMJs), axonal degeneration and neuronal death. Most ALS cases are linked to TDP-43 pathology, characterized by its mislocalization from the nucleus to the cytoplasm and the formation of phosphorylated aggregates. TDP-43 is a multifunctional DNA-binding/RNA-binding protein with roles in transcriptional and splicing regulation, RNA processing and RNA transport/subcellular localization.
Recently, we showed that TDP-43 co-localizes with the core stress granule component G3BP1 in axonal condensates of patients with ALS and mice. These TDP-43-G3BP1 condensates sequester RNA and inhibit local protein synthesis, resulting in mitochondrial malfunction and NMJ disruption with subsequent axonal degeneration. Furthermore, recent studies revealed aggregation of TDP-43 in peripheral motor axons of patients with ALS during initial diagnosis. Thus, axonal TDP-43 condensates exert pathological regulation over essential local synthesis events.
Here, we studied the localized accumulation of TDP-43 in axons and NMJs. Our findings highlight the presence of distal TDP-43 pathology in patients with SOD1 ALS and mouse models. We found that TDP-43 accumulates at NMJs due to aberrant local synthesis triggered by a reduction in miR-126a-5p within muscle extracellular vesicles. This chain of events ultimately initiates neurodegeneration. Notably, delivery of miR-126 is neuroprotective in neuromuscular co-cultures, delays TDP-43 accumulation at NMJs, and postpones the onset of motor symptoms in the SOD1G93A mouse model of ALS.
Link: https://doi.org/10.1038/s41593-025-02062-6
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