Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated wild-type TAR DNA-binding protein 43 (TDP-43). We show here that co-expression of mutant or wild-type TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein SOD1G85R-GFP in human cell cultures, and promotes synergistic axonopathy in zebrafish. Intriguingly, this pathological interaction is modulated by natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RNA-recognition motif RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce wild-type SOD1 misfolding in human cell cultures, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in human cell cultures, and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease.
List of abbreviationsALSamyotrophic lateral sclerosis
FALSfamilial amyotrophic lateral sclerosis
SOD1superoxide dismutase-1
TDP-43transactive response DNA-binding protein 43
GFPgreen fluorescent protein
TARDBPtransactive response DNA-binding protein 43 gene
G3BP1Ras GTPase-activating protein-binding protein 1
NLSnuclear localization sequence
NESnuclear export sequence
Hpfhours post-fertilization
Mnx1motor neuron and pancreas homeobox protein 1
SASAsolvent accessible surface area
FTDfrontotemporal dementia
scFvsingle-chain variable fragment
RACK1receptor for activated C kinase 1
DISC1disrupted-in-schizophrenia 1
© 2024 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.
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