Abstract
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 intra-muscular 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.
Highlights
Mislocalization of the predominantly nuclear RNA/DNA binding protein, TAR-DNA-binding-protein 43 (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
We tested the existence of axonal TDP-43 pathology in C9ORF72 ALS patient iPS-MNs39,40, as previously reported for cell-bodies[7]
We show that TDP-43 axonal accumulation elicits the formation of RNA and G3BP1 containing RNP-condensates in axons, interfering with axonal and pre-synaptic protein synthesis
Summary
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. Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disease characterized by neuromuscular junction (NMJ) disruption and motor neuron (MN) degeneration[1,2]. An important pathological hallmark in ALS patients is mislocalization of the primarily nuclear RNA and DNA binding protein TAR-DNA-binding-protein 43 (TDP-43) to the cytoplasm of MNs3–7. Mutations in TDP-43 were identified in a subset of ALS patients[11]. One key event which develops due to TDP-43 mislocalization is the formation of phase separated cytoplasmic condensates that alter RNA localization and translation[13,14,15,16,17]. ALS-associated mutations in TDP-43 directly interfere with mRNA transport[18,19]
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