TDP-43 is one of the more recently discovered problem proteins in the aging brain, capable of misfolding and aggregating in ways that promote neurodegeneration and the onset of dementia. This occurs to at least some degree in all older individuals, but where this aggregation is particularly pronounced it can give rise to conditions such as amyotrophic lateral sclerosis. Here, researchers report on their investigations of the biochemistry of this dysfunction, providing further evidence for TDP-43 aggregation to cause the onset and progression of amyotrophic lateral sclerosis.
Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intramuscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model.
In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development.